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Acetylcysteine solution (MUCOMYST)
SPL UNCLASSIFIED 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 a white crystalline powder which melts in the range of 104° to 110°C and has a very slight odor. The structural formula of acetylcysteine is:
Acetylcysteine Solution, USP is supplied as a sterile unpreserved solution (not for injection) in vials containing a 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.
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 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 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 apriori 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:
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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 liquefied 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
General
With the administration of acetylcysteine, the patient may observe initially 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 acetylcysteine in the opened bottle. The light purple color is the result of a chemical reaction which does not significantly affect safety or mucolytic efficacy 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 data1 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: Pregnancy Category B
Teratology: 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 or 35 minutes twice a day from the 16th through the 18th day of pregnancy. No teratogenic effects were observed among the offspring.
Teratology and a perinatal and 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.
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
General
Acetylcysteine Solution, USP is available in rubber stoppered glass vials containing 10 mL or 30 mL. The 20% solution may be diluted to a 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 a portion of the solution in a vial is used, store the remainder in a refrigerator and use for inhalation only within 96 hours.
Nebulization — Face Mask, Mouthpiece, Tracheostomy: When nebulized into a face mask, mouthpiece, or tracheostomy, 1 to 10 mL of the 20% solution or 2 to 20 mL of the 10% solution may be given every 2 to 6 hours; the recommended dose for most patients is 3 to 5 mL of the 20% solution or 6 to 10 mL of the 10% solution three to four 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 (using 10 or 20%) 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 a 10% to 20% 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 a 10% to 20% solution may be given every 1 to 4 hours by instillation into the tracheostomy.
Acetylcysteine 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 20% solution may then be instilled by means of a syringe connected to the catheter.
Acetylcysteine may also be given through a percutaneous intratracheal catheter. One to 2 mL of the 20% or 2 to 4 mL of the 10% solution every 1 to 4 hours may then be given by a syringe attached to the catheter.
Diagnostic Bronchograms: For diagnostic bronchial studies, 2 or 3 administrations of 1 to 2 mL of the 20% solution or 2 to 4 mL of the 10% solution should be given by nebulization or by instillation intratracheally, prior to the procedure.
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