Acetylcysteine (inhaled)

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.

The maintenance dose is then repeated at 4-hour intervals for a total of 17 doses. Monitor hepatic and renal function and electrolytes throughout the detoxification process. 2. Predetoxification acetaminophen level could not be obtained: Proceed as in A. 3. Predetoxification acetaminophen level is clearly in the nontoxic range (beneath the dashed line on the nomogram) and you know that acetaminophen overdose occurred at least 4 hours before the predetoxification acetaminophen plasma assays: Discontinue administration of acetylcysteine solution. 4.

DOSAGE AND ADMINISTRATION General Acetylcysteine solution is available in rubber stoppered glass vials containing 4 or 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. The 10% solution may be used undiluted.

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, store the remainder in a refrigerator and use for inhalation only 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 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 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 (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 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 20% 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 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, two to three 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. 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.

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 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 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 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.

PROLONGED NEBULIZATION When three fourths of the initial volume of acetylcysteine solution have been nebulized, a quantity of sterile water for injection (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 solution 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. [See table below.] 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 solution after mixing. Acetylcysteine solution, USP 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 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 solution 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 solution 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 Acetylcysteine solution, 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 treatment 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 solution in the treatment of acetaminophen overdose. WARNINGS Generalized urticaria has been observed rarely in patients receiving oral acetylcysteine solution for acetaminophen overdose.

If this occurs or other allergic symptoms appear, treatment with acetylcysteine solution 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 solution treatment should be discontinued to avoid further administration of nitrogenous substances.

There are no data indicating that acetylcysteine solution 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 solution 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 solution given accordingly.

Dilution of the acetylcysteine solution (see Preparation of Acetylcysteine solution for Oral Administration) minimizes the propensity of oral acetylcysteine solution to aggravate vomiting. ADVERSE REACTIONS Oral administration of acetylcysteine solution, especially in the large doses needed to treat acetaminophen overdose, may result in nausea, vomiting and other gastrointestinal symptoms.