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ACETYLCYSTEINE SOLUTION, USP 10% and 20%
Rx only
DESCRIPTION
Acetylcysteine is for inhalation (mucolytic agent) or oral administration (acetaminophen antidote), and available as sterile, unpreserved solutions (not for injection). The solutions contain 20% acetylcysteine with 0.05% edetate disodium, or 10% acetylcysteine with 0.025% edetate disodium, in Water for Injection. Sodium hydroxide and/or hydrochloric acid may be used to adjust pH to 6.0-7.5. Acetylcysteine is the N-acetyl derivative of the naturally occurring amino acid, cysteine. The compound is a white crystalline powder with the molecular formula C5H9NO3S, a molecular weight of 163.2, and chemical name of N-acetyl-L-cysteine.
Acetylcysteine has the following structural formula:
This product contains the following inactive ingredients: edetate disodium, sodium hydroxide, and Water for Injection.
Acetylcysteine As A Mucolytic Agent
CLINICAL PHARMACOLOGY
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 mucus 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.
INDICATIONS AND USAGE
Acetylcysteine is indicated as adjuvant therapy for patients with abnormal, viscid, or inspissated mucous secretions in such conditions as:
- Chronic bronchopulmonary disease (chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis and primary amyloidosis of the lung)
- Acute bronchopulmonary disease (pneumonia, bronchitis, tracheobronchitis)
- Pulmonary complications of cystic fibrosis
- Tracheostomy care
- Pulmonary complications associated with surgery
- Use during anesthesia
- Post-traumatic chest conditions
- Atelectasis due to mucous obstruction
- Diagnostic bronchial studies (bronchograms, bronchospirometry, and bronchial wedge catheterization)
CONTRAINDICATIONS
Acetylcysteine is contraindicated in those patients who are sensitive to it.
WARNINGS
After proper administration of acetylcysteine, an increased volume of liquified bronchial secretions may occur. When cough is inadequate, the airway must be maintained open by mechanical suction if necessary. When there is a mechanical block due to foreign body or local accumulation, the airway should be cleared by endotracheal aspiration, with or without bronchoscopy. Asthmatics under treatment with acetylcysteine should be watched carefully. 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.
PRECAUTIONS
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Pregnancy
ADVERSE REACTIONS
Adverse effects have included stomatitis, nausea, vomiting, fever, rhinorrhea, drowsiness, clamminess, chest tightness, and bronchoconstriction. Clinically overt acetylcysteine induced bronchospasm occurs infrequently and unpredictably even in patients with asthmatic bronchitis or bronchitis complicating bronchial asthma.
Acquired sensitization to acetylcysteine has been reported rarely. Reports of sensitization in patients have not been confirmed by patch testing. Sensitization has been confirmed in several inhalation therapists who reported a history of dermal eruptions after frequent and extended exposure to acetylcysteine.
Reports of irritation to the tracheal and bronchial tracts have been received and although hemoptysis has occurred in patients receiving acetylcysteine such findings are not uncommon in patients with bronchopulmonary disease and a causal relationship has not been established.
DOSAGE AND ADMINISTRATION
COMPATIBILITY
The physical and chemical compatibility of acetylcysteine solutions with certain other drugs that might be concomitantly administered by nebulization, direct instillation, or topical application has been studied.
Acetylcysteine should not be mixed with certain antibiotics. For example, the antibiotics tetracycline hydrochloride, oxytetracycline hydrochloride, and erythromycin lactobionate were found to be incompatible when mixed in the same solution. These agents may be administered from separate solutions if administration of these agents is desirable.
The supplying of these data should not be interpreted as a recommendation for combining acetylcysteine with other drugs. The table is not presented as positive assurance that no incompatibility will be present, since these data are based only on short-term compatibility studies done in the Mead Johnson Research Center. Manufactures may change their formulation, and this could alter compatibilities. These data are intended to serve only as a guide for predicting compounding problems.
If it is deemed advisable to prepare an admixture, it should be administered as soon as possible after preparation. Do not store unused mixtures.
- The rating, Incompatible, is based on the formation of a precipitate, a change in clarity, immiscibility, or a rapid loss of potency of acetylcysteine or the active ingredient of the PRODUCT AND/OR AGENT in the admixture.
- The rating, Compatible, means that there was no significant physical change in the admixture when compared with a control solution of the PRODUCT AND/OR AGENT, and that there was no predicted chemical incompatibility. All of the admixtures have been tested for short-term chemical compatibility by assaying for the concentration of acetylcysteine after mixing.
- The active ingredient in the PRODUCT AND/OR AGENT was also assayed after mixing. Some of the admixtures developed minor physical changes which were considered to be insufficient to rate the admixture incompatible. These are uled in footnotes 3, 4, and 5.
- A strong odor developed after storage for 24 hours at room temperature.
- The admixture was a slightly darker shade of yellow than a control solution of the PRODUCT AND/OR AGENT.
- A light tan color developed after storage for 24 hours at room temperature.
- Entries are final concentrations. Values in parentheses relate volumes of acetylcysteine solutions to volume of test solutions.
Acetylcysteine As An Antidote For Acetaminophen Overdose
CLINICAL PHARMACOLOGY
(Antidotal) Acetaminophen is rapidly absorbed from the upper gastrointestinal tract with peak plasma levels occurring between 30 and 60 minutes after therapeutic doses and usually within 4 hours following an overdose. The parent compound, which is nontoxic, is extensively metabolized in the liver to form principally the sulfate and glucuronide conjugates which are also nontoxic and are rapidly excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite which preferentially conjugates with hepatic glutathione to form the nontoxic cysteine and mercapturic acid derivatives which are then excreted by the kidney. Therapeutic doses of acetaminophen do not saturate the glucuronide and sulfate conjugation pathways and do not result in the formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the P-450 pathway. The increased formation of reactive metabolite may deplete the hepatic stores of glutathione with subsequent binding of the metabolite to protein molecules within the hepatocyte resulting in cellular necrosis.
Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. Its effectiveness depends on early oral administration, with benefit seen principally in patients treated within 16 hours of the overdose. Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite.
INDICATIONS AND USAGE
Acetylcysteine, administered orally, is indicated as an antidote to prevent or lessen hepatic injury which may occur following the ingestion of a potentially hepatotoxic quantity of acetaminophen.
It is essential to initiate as soon as possible after the overdose and, in any case, within 24 hours of ingestion.
CONTRAINDICATIONS
There are no contraindications to oral administration of acetylcysteine in the treatment of acetaminophen overdose.
WARNINGS
Generalized urticaria has been observed rarely in patients receiving oral acetylcysteine for acetaminophen overdose. If this occurs or other allergic symptoms appear, treatment with acetylcysteine should be discontinued unless it is deemed essential and the allergic symptoms can be otherwise controlled.
If encephalopathy due to hepatic failure becomes evident, acetylcysteine treatment should be discontinued to avoid further administration of nitrogenous substances. There are no data indicating that acetylcysteine influences hepatic failure, but this remains a theoretical possibility.
PRECAUTIONS
Occasionally severe and persistent vomiting occurs as a symptom of acute acetaminophen overdose. Treatment with oral acetylcysteine may aggravate the vomiting. Patients at risk of gastric hemorrhage (e.g., esophageal varices, peptic ulcers, etc.) should be evaluated concerning the risk of upper gastrointestinal hemorrhage versus the risk of developing hepatic toxicity, and treatment with acetylcysteine given accordingly.
Dilution of the acetylcysteine (see PREPARATION OF ACETYLCYSTEINE FOR ORAL ADMINISTRATION) minimizes the propensity of oral acetylcysteine to aggravate vomiting.
ADVERSE REACTIONS
Oral administration of acetylcysteine, especially in the large doses needed to treat acetaminophen overdose, may result in nausea, vomiting and other gastrointestinal symptoms. Rash with or without mild fever has been observed rarely.
DOSAGE AND ADMINISTRATION
ACETAMINOPHEN ASSAYS - INTERPRETATION AND METHODOLOGY
The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. However, the reported history of the quantity of a drug ingested as an overdose is often inaccurate and is not a reliable guide to therapy of the overdose. THEREFORE, PLASMA OR SERUM ACETAMINOPHEN CONCENTRATIONS, DETERMINED AS EARLY AS POSSIBLE, BUT NO SOONER THAN 4 HOURS FOLLOWING AN ACUTE OVERDOSE, ARE ESSENTIAL IN ASSESSING THE POTENTIAL RISK OF HEPATOTOXICITY. IF AN ASSAY FOR ACETAMINOPHEN CANNOT BE OBTAINED, IT IS NECESSARY TO ASSUME THAT THE OVERDOSE IS POTENTIALLY TOXIC.
HOW SUPPLIED
Acetylcysteine Solution USP, 10% (100 mg Acetylcysteine per mL). Sterile, NOT FOR INJECTION.
NDC 61703-203-32 10 mL vial Box of 10
NDC 61703-203-31 30 mL vial Box of 10
Acetylcysteine Solution USP, 20% (200 mg Acetylcysteine per mL). Sterile, NOT FOR INJECTION.
NDC 61703-204-32 10 mL vial Box of 10
NDC 61703-204-31 30 mL vial Box of 10
The 20% solution may be diluted to a lesser concentration with either Sodium Chloride for Injection, Sodium Chloride for Inhalation, Sterile Water for Injection, or Sterile Water for Inhalation. The 10% solution may be used undiluted.
Store unopened vials at controlled room temperature, between 15°-30°C (59°-86°F).
Acetylcysteine does not contain an antimicrobial agent, and care must be taken to minimize contamination of the sterile solution. Dilutions of acetylcysteine should be used freshly prepared and utilized within one hour. If only a portion of the solution in a vial is used, store the remaining undiluted portion in a refrigerator and use within 96 hours.
REFERENCES
- Bonanomi L. Gazzaniga A. Toxicological, pharmacokinetic and metabolic studies on acetylcysteine. Eur J Respir Dis 1961; 61 (suppl. III): 45-51.
- Am Rev Respir Dis 1960; 82:627-639.
A change in color may occur after opening. This does not change the efficacy of the drug.
Manufactured for:
Mayne Pharma ( USA) Inc.
Paramus, NJ 07652
By: Mayne Pharma (PR) Inc.
Aguadilla, Puerto Rico 00604
Rev. September 2004 PI007/KI