Acetylcysteine

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.

CONTRAINDICATIONS Acetylcysteine is contraindicated in those patients who are sensitive to it.

DESCRIPTION Acetylcysteine solution, USP is for inhalation (mucolytic agent) or oral administration (acetaminophen antidote), available as a sterile, unpreserved solution (NOT FOR INJECTION). The solution contains 20% (200 mg/mL) acetylcysteine, with disodium edetate in water for injection. The solution also contains sodium hydroxide and may contain hydrochloric acid to adjust pH (range 6.0 - 7.5). Acetylcysteine is the N-acetyl derivative of the naturally-occurring amino acid, L-cysteine. The compound is a white crystalline powder with the molecular formula C 5 H 9 NO 3 S, 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: disodium edetate, sodium hydroxide and water for injection. Structural Formula

DOSAGE AND ADMINISTRATION General Acetylcysteine solution is available in rubber stoppered glass vials containing 30 mL. The 20% solution may be diluted to a lesser concentration with either Sodium Chloride Injection, Sodium Chloride Inhalation Solution, Sterile Water for Injection, or Sterile Water for Inhalation. Acetylcysteine solution does not contain an antimicrobial agent, and care must be taken to minimize contamination of the sterile solution. If only a portion of the solution in a vial is used for inhalation, store the remainder in a refrigerator and use within 96 hours. Nebulization-face mask, mouth piece, tracheostomy When nebulized into a face mask, mouth piece, or tracheostomy, 1 to 10 mL of the solution may be given every 2 to 6 hours; the recommended dose for most patients is 3 to 5 mL of the solution 3 to 4 times a day. Nebulization tent, Croupette In special circumstances it may be necessary to nebulize into a tent or Croupette, and this method of use must be individualized to take into account the available equipment and the patient's particular needs. This form of administration requires very large volumes of the solution, occasionally as much as 300 mL during a single treatment period. If a tent or Croupette must be used, the recommended dose is the volume of acetylcysteine solution that will maintain a very heavy mist in the tent or Croupette for the desired period. Administration for intermittent or continuous prolonged periods, including overnight, may be desirable. Direct Instillation When used by direct instillation, 1 to 2 mL of solution may be given as often as every hour. When used for the routine nursing care of patients with tracheostomy, 1 to 2 mL of solution may be given every 1 to 4 hours by instillation into the tracheostomy. Acetylcysteine solution may be introduced directly into a particular segment of the bronchopulmonary tree by inserting (under local anesthesia and direct vision) a small plastic catheter into the trachea. Two to 5 mL of the solution may then be instilled by means of a syringe connected to the catheter. Acetylcysteine solution may also be given through a percutaneous intratracheal catheter. One to 2 mL of the solution every 1 to 4 hours may then be given by a syringe attached to the catheter. Diagnostic Bronchograms For diagnostic bronchial studies, two or three administrations of 1 to 2 mL of the solution should be given by nebulization or by instillation intratracheally, prior to the procedure. Administration of Aerosol Materials Acetylcysteine solution may be administered using conventional nebulizers made of plastic or glass. Certain materials used in nebulization equipment react with acetylcysteine solution. The most reactive of these are certain metals (notably iron and copper) and rubber. Where materials may come into contact with acetylcysteine solution, parts made of the following acceptable materials should be used: glass, plastic, aluminum, anodized aluminum, chromed metal, tantalum, sterling silver, or stainless steel. Silver may become tarnished after exposure, but this is not harmful to the drug action or to the patient. Nebulizing Gases Compressed tank gas (air) or an air compressor should be used to provide pressure for nebulizing the solution. Oxygen may also be used but should be used with the usual precautions in patients with severe respiratory disease and CO 2 retention. Apparatus Acetylcysteine solution is usually administered as fine nebulae and the nebulizer used should be capable of providing optimal quantities of a suitable range of particle sizes. Commercially available nebulizers will produce nebulae of acetylcysteine solution satisfactory for retention in the respiratory tract. Most of the nebulizers tested will supply a high proportion of the drug solution as particles of less than 10 microns in diameter. Mitchell 2 has shown that particles less than 10 microns should be retained in the respiratory tract satisfactorily. Various intermittent positive pressure breathing devices nebulized acetylcysteine solution with a satisfactory efficiency including: No. 40 De Vilbiss (The De Vilbiss Co., Somerset, Pennsylvania), and the Bennett Twin-Jet Nebulizer (Puritan Bennett Corp., Oak at 13th., Kansas City, Missouri). The nebulized solution may be inhaled directly from the nebulizer. Nebulizers may also be attached to the plastic face masks or plastic mouthpieces. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines. The nebulizing equipment should be cleaned immediately after use because the residues may clog the smaller orifices or corrode metal parts. Hand bulbs are not recommended for routine use in nebulizing acetylcysteine solution because their output is generally too small. Also, some hand-operated nebulizers deliver particles that are larger than optimum for inhalation therapy. Acetylcysteine solution should not be placed directly into the chamber of a heated (hot pot) nebulizer. A heated nebulizer may be part of the nebulization assembly to provide a warm saturated atmosphere if the acetylcysteine solution aerosol is introduced by means of a separate unheated nebulizer. Usual precautions for administration of warm saturated nebulae should be observed. The nebulized solution may be breathed directly from the nebulizer. Nebulizers may also be attached to plastic face masks, plastic face tents, plastic mouth pieces, conventional plastic oxygen tents, or head tents. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines. The nebulizing equipment should be cleaned immediately after use, otherwise the residues may occlude the fine orifices or corrode metal parts. Prolonged Nebulization When three fourths of the initial volume of acetylcysteine solution has been nebulized, a quantity of Sterile Water for Injection, USP (approximately equal to the volume of solution remaining) should be added to the nebulizer. This obviates any concentration of the agent in the residual solvent remaining after prolonged nebulization. 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 solution 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. Manufacturers may change their formulations, 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. IN VITRO COMPATIBILITY 1 TESTS OF ACETYLCYSTEINE Product and/or Agent Compatibility Rating Ratio Tested 6 Acetylcysteine Product or Agent ANESTHETIC GAS Halothane Compatible 20% Infinite Nitrous Oxide Compatible 20% Infinite ANESTHETIC LOCAL Cocaine HCl Compatible 10% 5% Lidocaine HCl Compatible 10% 2% Tetracaine HCl Compatible 10% 1% ANTIBACTERIALS (A parenteral form of each antibiotic was used) Bacitracin 2,3 (mix and use at once) Compatible 10% 5,000 U/mL Chloramphenicol Sodium Succinate Compatible 20% 20 mg/mL Carbenicillin Disodium2 (mix and use at once) Compatible 10% 125 mg/mL Gentamicin Sulfate 2 Compatible 10% 20 mg/mL Kanamycin Sulfate 2 (mix and use at once) Compatible 10% 167 mg/mL Compatible 17% 85 mg/mL Lincomycin HCl 2 Compatible 10% 150 mg/mL Neomycin Sulfate 2 Compatible 10% 100 mg/mL Novobiocin Sodium 2 Compatible 10% 25 mg/mL Penicillin G Potassium 2 (mix and use at once) Compatible 10% 25,000 U/mL Compatible 10% 100,000 U/mL Polymyxin B Sulfate 2 Compatible 10% 50,000 U/mL Cephalothin Sodium Compatible 10% 110 mg/mL Colistimethate Sodium2 (mix and use at once) Compatible 10% 37.5 mg/mL Vancomycin HCl 2 Compatible 10% 25 mg/mL Amphotericin B Incompatible 4% - 15% 1.0 - 4.0 mg/mL Chlortetracycline HCl 2 Incompatible 10% 12.5 mg/mL Erythromycin Lactobionate Incompatible 10% 15 mg/mL Oxytetracycline HCl Incompatible 10% 12.5 mg/mL Ampicillin Sodium Incompatible 10% 50 mg/mL Tetracycline HCl Incompatible 10% 12.5 mg/mL BRONCHODILATORS Isoproterenol HCl 2 Compatible 3.0% 0.5% Isoproterenol HCl 2 Compatible 10% 0.05% Isoproterenol HCl 2 Compatible 20% 0.05% Isoproterenol HCl Compatible 13.3% (2 parts) .33% (1 part) Isoetharine HCl Compatible 13.3% (2 parts) (1 part) Epinephrine HCl Compatible 13.3% (2 parts) 0.33% (1 part) CONTRAST MEDIA Iodized Oil Incompatible 20%/20 mL 40%/10 mL DECONGESTANTS Phenylephrine HCl 2 Compatible 3.0% 0.25% Phenylephrine HCl Compatible 13.3% (2 parts) 0.17% (1 part) ENZYMES Chymotrypsin Incompatible 5% 400 γ/mL Trypsin Incompatible 5% 400 γ/mL SOLVENTS Alcohol Compatible 12% 10% - 20% Propylene Glycol Compatible 3% 10% STEROIDS Dexamethasone Sodium Phosphate Compatible 16% 0.8 mg/mL Prednisolone Sodium Phosphate 2 Compatible 16.7% 3.3 mg/mL OTHER AGENTS Hydrogen Peroxide Incompatible (All ratios) Sodium Bicarbonate Compatible 20% (1 part) 4.2% (1 part)

INDICATIONS AND USAGE Acetylcysteine solution, USP 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)

WARNINGS After proper administration of acetylcysteine, an increased volume of liquified bronchial secretions may occur. When cough is inadequate, the open 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.

Drug Interactions Drug stability and safety of acetylcysteine when mixed with other drugs in a nebulizer have not been established.

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 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.

20191001

1

Acetylcysteine Acetylcysteine Solution ACETYLCYSTEINE ACETYLCYSTEINE EDETATE DISODIUM SODIUM HYDROXIDE HYDROCHLORIC ACID WATER

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis Carcinogenicity studies in laboratory animals have not been performed with acetylcysteine alone, nor with acetylcysteine in combination with isoproterenol. Long-term oral studies of acetylcysteine alone in rats (12 months of treatment followed by 6 months of observation) at doses up to 1,000 mg/kg/day (5.2 times the human mucolytic dose) provided no evidence of oncogenic activity. Mutagenesis Published data 1 indicate that acetylcysteine is not mutagenic in the Ames test, both with and without metabolic activation. Impairment of Fertility A reproductive toxicity test to assess potential impairment of fertility was performed with acetylcysteine (10%) combined with isoproterenol (0.05%) and administered as an aerosol into a chamber of 12.43 cubic meters. The combination was administered for 25, 30, or 35 minutes twice a day for 68 days before mating, to 200 male and 150 female rats; no adverse effects were noted in dams or pups. Females after mating were continued on treatment for the next 42 days. Reproductive toxicity studies of acetylcysteine in the rat given oral doses of acetylcysteine up to 1,000 mg/kg (5.2 times the human mucolytic dose) have also been reported in the literature.1 The only adverse effect observed was a slight non-dose-related reduction in fertility at dose levels of 500 or 1,000 mg/kg/day (2.6 or 5.2 times the human mucolytic dose) in the Segment I study.

ANDA205643

Acetylcysteine

Acetylcysteine Solution

51754-0105

HUMAN PRESCRIPTION DRUG

ORAL,RESPIRATORY (INHALATION)

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL-Vial Rx Only NDC 51754-0105-1 Acetylcysteine Solution, USP 20% (200 mg/mL) For Inhalation (Mucolytic Agent) or Oral Administration (Acetaminophen Antidote) NOT FOR INJECTION PRESERVATIVE FREE 30 mL Vial Vial Label

Acetylcysteine as a Mucolytic Agent

REFERENCES 1. Bonanomi L, Gazzaniga A. Toxicological, pharmacokinetic and metabolic studies on acetylcysteine. Eur J Respir Dis , 1981; 61 (Suppl III): 45-51. 2. Am Rev Respir Dis , 1960; 82:627-639. Manufactured and Distributed by: Exela Pharma Sciences, LLC Lenoir, NC 28645 Revised 05/2021 Logo

Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman.

HOW SUPPLIED Acetylcysteine Solution, USP is available in rubber stoppered glass vials containing 30 mL. 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. Acetylcysteine is sterile, not for injection and can be used for inhalation (mucolytic agent) or oral administration (acetaminophen antidote). Acetylcysteine solution is not for parenteral injection. It is available as: Acetylcysteine Solution, USP 20% (200 mg acetylcysteine per mL). Sterile, not for injection. NDC 51754-0105-8 Cartons of three 30 mL vials

General With the administration of acetylcysteine the patient may initially observe a slight disagreeable odor that is soon not noticeable. With a face mask there may be stickiness on the face after nebulization. This is easily removed by washing with water. Under certain conditions, a color change may occur in the opened bottle of acetylcysteine. The light purple color is the result of a chemical reaction which does not significantly affect the safety or mucolytic effectiveness of acetylcysteine. Continued nebulization of acetylcysteine solution with a dry gas will result in an increased concentration of the drug in the nebulizer because of evaporation of the solvent. Extreme concentration may impede nebulization and efficient delivery of the drug. Dilution of the nebulizing solution with appropriate amounts of Sterile Water for Injection, USP, as concentration occurs, will obviate this problem.

PRECAUTIONS General With the administration of acetylcysteine the patient may initially observe a slight disagreeable odor that is soon not noticeable. With a face mask there may be stickiness on the face after nebulization. This is easily removed by washing with water. Under certain conditions, a color change may occur in the opened bottle of acetylcysteine. The light purple color is the result of a chemical reaction which does not significantly affect the safety or mucolytic effectiveness of acetylcysteine. Continued nebulization of acetylcysteine solution with a dry gas will result in an increased concentration of the drug in the nebulizer because of evaporation of the solvent. Extreme concentration may impede nebulization and efficient delivery of the drug. Dilution of the nebulizing solution with appropriate amounts of Sterile Water for Injection, USP, as concentration occurs, will obviate this problem. Drug Interactions Drug stability and safety of acetylcysteine when mixed with other drugs in a nebulizer have not been established. Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis Carcinogenicity studies in laboratory animals have not been performed with acetylcysteine alone, nor with acetylcysteine in combination with isoproterenol. Long-term oral studies of acetylcysteine alone in rats (12 months of treatment followed by 6 months of observation) at doses up to 1,000 mg/kg/day (5.2 times the human mucolytic dose) provided no evidence of oncogenic activity. Mutagenesis Published data 1 indicate that acetylcysteine is not mutagenic in the Ames test, both with and without metabolic activation. Impairment of Fertility A reproductive toxicity test to assess potential impairment of fertility was performed with acetylcysteine (10%) combined with isoproterenol (0.05%) and administered as an aerosol into a chamber of 12.43 cubic meters. The combination was administered for 25, 30, or 35 minutes twice a day for 68 days before mating, to 200 male and 150 female rats; no adverse effects were noted in dams or pups. Females after mating were continued on treatment for the next 42 days. Reproductive toxicity studies of acetylcysteine in the rat given oral doses of acetylcysteine up to 1,000 mg/kg (5.2 times the human mucolytic dose) have also been reported in the literature.1 The only adverse effect observed was a slight non-dose-related reduction in fertility at dose levels of 500 or 1,000 mg/kg/day (2.6 or 5.2 times the human mucolytic dose) in the Segment I study. Pregnancy: Teratogenic Effects: In a teratology study of acetylcysteine in the rabbit, oral doses of 500 mg/kg/day (2.6 times the human mucolytic dose) were administered to pregnant does by intubation on days 6 through 16 of gestation. Acetylcysteine was found to be nonteratogenic under the conditions of the study. In the rabbit, two groups (one of 14 and one of 16 pregnant females) were exposed to an aerosol of 10% acetylcysteine and 0.05% isoproterenol hydrochloride for 30 and 35 minutes twice a day from the 6th through the 18th day of pregnancy. No teratogenic effects were observed among the offspring. Teratology and a perinatal or postnatal toxicity study in rats were performed with a combination of acetylcysteine and isoproterenol administered by the inhalation route. In the rat, two groups of 25 pregnant females each were exposed to the aerosol for 30 and 35 minutes, respectively, twice a day from the 6th through the 15th day of gestation. No teratogenic effects were observed among the offspring. In the pregnant rat (30 rats per group), twice-daily exposure to an aerosol of acetylcysteine and isoproterenol for 30 or 35 minutes from the 15th day of gestation through the 21st day postpartum was without adverse effect on dams or newborns. Reproduction studies of acetylcysteine with isoproterenol have been performed in rats and of acetylcysteine alone in rabbits at doses up to 2.6 times the human dose. These have revealed no evidence of impaired fertility or harm to the fetus due to acetylcysteine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies may not always be predictive of human responses, this drug should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman.