ADVERSE REACTIONS SECTION.

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 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 causal relationship has not been established.

INDICATIONS & USAGE SECTION.

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 fibrosisTracheostomy carePulmonary complications associated with surgeryUse during anesthesiaPost-traumatic chest conditionsAtelectasis due to mucous obstructionDiagnostic bronchial studies (bronchograms, bronchospirometry, and bronchial wedge catheterization). 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 fibrosisTracheostomy carePulmonary complications associated with surgeryUse during anesthesiaPost-traumatic chest conditionsAtelectasis due to mucous obstructionDiagnostic bronchial studies (bronchograms, bronchospirometry, and bronchial wedge catheterization).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 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 data1 indicate that acetylcysteine is not mutagenic in the Ames test, both with and without metabolic activation.Impairment of Fertility: 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 chamber of 12.43 cubic meters. The combination was administered for 25, 30, or 35 minutes twice 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 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 study.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. The viscosity of pulmonary mucous secretions depends on the concentrations of mucoprotein and, to 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 and 9.Acetylcysteine undergoes rapid deacetylation in vivo to yield cysteine or oxidation to yield diacetylcysteine. 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 priori from random patient population. Even when patients are known to have reacted previously to the inhalation of an acetylcysteine aerosol, they may not react during 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 bronchodilator given by nebulization. If bronchospasm progresses, the medication should be discontinued immediately.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

DESCRIPTION. Acetylcysteine is the nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine. Chemically, it is N-acetyl-L-cysteine.The compound is white crystalline powder which melts in the range of 104 to 110C and has very slight odor. The structural formula of acetylcysteine is:C5H9NO3S M.W.=163.19Acetylcysteine Solution, USP is supplied as sterile unpreserved solution (not for injection) in vials containing 10% (100 mg/mL) or 20% (200 mg/mL) solution of acetylcysteine as the sodium salt. The inactive ingredients are edetate disodium, sodium hydroxide and Sterile Water for Injection, USP. The pH of the solution ranges from 6.0 to 7.5. It is administered by inhalation or direct instillation for mucolysis, or orally for acetaminophen overdosage.. structural formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. General. Acetylcysteine Solution, USP is available in rubber stoppered glass vials containing 10 mL or 30 mL. The 20% solution may be diluted to lesser concentration with either Sodium Chloride Injection, Sodium Chloride for Inhalation, Sterile Water for Injection, or Sterile Water for Inhalation. The 10% solution may be used undiluted.Acetylcysteine does not contain an antimicrobial agent, and care must be taken to minimize contamination of the sterile solution. If only portion of the solution in vial is used, store the remainder in refrigerator and use for inhalation only within 96 hours.Nebulization -- Face Mask, Mouthpiece, Tracheostomy: When nebulized into face mask, mouthpiece, or tracheostomy, to 10 mL of the 20% solution or to 20 mL of the 10% solution may be given every to hours; the recommended dose for most patients is to mL of the 20% solution or to 10 mL of the 10% solution three to four times day.Nebulization -- Tent, Croupette: In special circumstances it may be necessary to nebulize into tent or Croupette, and this method of use must be individualized to take into account the available equipment and the patients particular needs. This form of administration requires very large volumes of the solution, occasionally as much as 300 mL during single treatment period.If tent or Croupette must be used, the recommended dose is the volume of acetylcysteine (using 10 or 20%) that will maintain 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, to mL of 10% to 20% solution may be given as often as every hour.When used for the routine nursing care of patients with tracheostomy, to mL of 10% to 20% solution may be given every to hours by instillation into the tracheostomy.Acetylcysteine may be introduced directly into particular segment of the bronchopulmonary tree by inserting (under local anesthesia and direct vision) small plastic catheter into the trachea. Two to mL of the 20% solution may then be instilled by means of syringe connected to the catheter.Acetylcysteine may also be given through percutaneous intratracheal catheter. One to mL of the 20% or to mL of the 10% solution every to hours may then be given by syringe attached to the catheter.Diagnostic Bronchograms: For diagnostic bronchial studies, or administrations of to mL of the 20% solution or to mL of the 10% 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. 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 usual precautions in patients with severe respiratory disease and CO2 retention.Apparatus: Acetylcysteine solution is usually administered as fine nebulae and the nebulizer used should be capable of providing optimal quantities of suitable range of particle sizes.Commercially available nebulizers will produce nebulae of acetylcysteine satisfactory for retention in the respiratory tract. Most of the nebulizers tested will supply high proportion of the drug solution as particles of less than 10 microns in diameter. Mitchell2 has shown that particles less than 10 microns should be retained in the respiratory tract satisfactorily.Various intermittent positive pressure breathing devices nebulized acetylcysteine with satisfactory efficiency including: No:40 Da Vilbiss (The Da Vilbiss Co., Somerset, PA) and the Bennett Twin-Jet Nebulizer (Puritan Bennett Corp., Oak at 13th, Kansas City, MO).The nebulized solution may be inhaled directly from the nebulizer. Nebulizers may also be attached to 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 for nebulizing acetylcysteine 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 heated (hot pot) nebulizer. heated nebulizer may be part of the nebulization assembly to provide warm saturated atmosphere if the acetylcysteine aerosol is introduced by means of 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 mouthpieces, 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, 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 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 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 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.

DRUG INTERACTIONS SECTION.

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

GENERAL PRECAUTIONS SECTION.

General. With the administration of acetylcysteine, the patient may observe initially slight disagreeable odor that is soon not noticeable. With face mask there may be stickiness on the face after nebulization. This is easily removed by washing with water.Under certain conditions, color change may occur in acetylcysteine in the opened bottle. The light purple color is the result of chemical reaction which does not significantly affect safety or mucolytic efficacy of acetylcysteine.Continued nebulization of acetylcysteine solution with 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.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Acetylcysteine Solution, USP, is available in rubber stopped glass vials containing 10 or 30 mL. The 20% solution may be diluted to 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.Acetycysteine is sterile, not for injection and can be used for inhalation (mucolytic agent) or oral administration (acetaminophen antidote). It is available as follows:20% Acetylcysteine Solution, USP (200 mg acetylcysteine per mL). NDC 54868-5670-0 x 30 mL vial Store unopened vials at controlled room temperature, 15 to 30C (59 to 86F).Acetylcysteine Solution, USP 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 portion of the solution in vial is used, store the remaining undiluted portion in refrigerator and use within 96 hours.

NURSING MOTHERS SECTION.

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 nursing woman.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

VIAL LABEL 20%, 30 mL. Vial Label 20%, 30 mL. Vial label for Acetylcysteine Solution, USP 20%, 30 mL.

PRECAUTIONS SECTION.

PRECAUTIONS. General. With the administration of acetylcysteine, the patient may observe initially slight disagreeable odor that is soon not noticeable. With face mask there may be stickiness on the face after nebulization. This is easily removed by washing with water.Under certain conditions, color change may occur in acetylcysteine in the opened bottle. The light purple color is the result of chemical reaction which does not significantly affect safety or mucolytic efficacy of acetylcysteine.Continued nebulization of acetylcysteine solution with 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 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 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 data1 indicate that acetylcysteine is not mutagenic in the Ames test, both with and without metabolic activation.Impairment of Fertility: 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 chamber of 12.43 cubic meters. The combination was administered for 25, 30, or 35 minutes twice 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 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 study.. Pregnancy. Teratogenic Effects: Pregnancy Category B. Teratology: In 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 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 or 35 minutes twice day from the 16th through the 18th day of pregnancy. No teratogenic effects were observed among the offspring.Teratology and perinatal and postnatal toxicity study in rats were performed with 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 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 nursing woman.

PREGNANCY SECTION.

Pregnancy. Teratogenic Effects: Pregnancy Category B. Teratology: In 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 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 or 35 minutes twice day from the 16th through the 18th day of pregnancy. No teratogenic effects were observed among the offspring.Teratology and perinatal and postnatal toxicity study in rats were performed with 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 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.

REFERENCES SECTION.

REFERENCES. Bonanomi L, Gazzaniga A. Toxicological pharmacokinetic and metabolic studies on acetylcysteine. Eur Respir Dis 1981 61 (Suppl III) :45-51.Amer Rev Resp Dis 1960 82 :627-639.. Bonanomi L, Gazzaniga A. Toxicological pharmacokinetic and metabolic studies on acetylcysteine. Eur Respir Dis 1981 61 (Suppl III) :45-51.. Amer Rev Resp Dis 1960 82 :627-639.

STORAGE AND HANDLING SECTION.

Store unopened vials at controlled room temperature, 15 to 30C (59 to 86F).Acetylcysteine Solution, USP 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 portion of the solution in vial is used, store the remaining undiluted portion in refrigerator and use within 96 hours.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects: Pregnancy Category B. Teratology: In 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 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 or 35 minutes twice day from the 16th through the 18th day of pregnancy. No teratogenic effects were observed among the offspring.Teratology and perinatal and postnatal toxicity study in rats were performed with 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 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.

WARNINGS SECTION.

WARNINGS. After proper administration of acetylcysteine, an increased volume of liquefied bronchial secretions may occur. When cough is inadequate, the airway must be maintained open by mechanical suction if necessary. When there is 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 bronchodilator given by nebulization. If bronchospasm progresses, the medication should be discontinued immediately.