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acetylcysteine solution, USP Dosage and Administration

DOSAGE AND ADMINISTRATION

General

Acetylcysteine Solution 10% and 20% is available in glass vials containing 30 mL. The 20% solution may be diluted to a lesser concentration with either Sodium Chloride Inhalation Solution; Sodium Chloride Injection; or Sterile Water for Injection, or Sterile Water for Inhalation. The 10% solution may be used undiluted.

Storage of Opened Vials

This product 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 (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% or 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.

Administration of Aerosol

Materials

Acetylcysteine 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 material 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 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 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 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 because their output is generally too small. Also, some hand-operated nebulizers deliver particles that are larger than optimum for inhalation therapy.

Acetylcysteine 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 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 (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 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. 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.

1.  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.
2.  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 admixtures incompatible. These are listed in footnotes 3, 4, and 5.
3.  A strong odor developed after storage for 24 hours at room temperature.
4.  The admixture was a slightly darker shade of yellow than a control solution of the PRODUCT AND/OR AGENT.
5.  A light tan color developed after storage for 24 hours at room temperature.
6.  Entries are final concentrations. Values in parentheses relate volumes of acetylcysteine solutions to volume of test solutions.

IN VITRO COMPATIBILITY1 TESTS OF ACETYLCYSTEINE

RATIO TESTED6

PRODUCT AND/OR AGENT

COMPATIBILITY

RATING

ACETYL-

CYSTEINE

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)

Bacitracin2.3 (mix and use at once)

Compatible

10%

5,000 U/mL

Chloramonenicol Sodium Succinate

Compatible

20%

20 mg/mL

Carbenicillin Disodium2

   (mix and use at once)

Compatible

 

10%

 

125 mg/mL

Gentamicin Sulfate2

Compatible

10%

20 mg/mL

Kanamycin Sulfate2

   (mix and use at once)

 

Compatible

 

10%

 

167 mg/mL

Compatible

17%

85 mg/mL

Lincomycin HCl2

Compatible

10%

150 mg/mL

Neomycin Sulfate2

Compatible

10%

100 mg/mL

Novobiocin Sodium2

Compatible

10%

25 mg/mL

Penicillin G Potassium2

   (mix and use at once)

Compatible

Compatible

10%

10%

25,000 U/mL

100,000 U/mL

Polymyxin B Sulfate2

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 HCl2

Compatible

10%

25 mg/mL

Amphotercin B

Incompatible

4%-15%

1-4 mg/mL

Chlortetracycline HCl2

Incompatible

10%

12.5 mg/mL

Erythromycin Lactobionate

Incompatible

10%

15 mg/mL

Oxytetracycline HCl

Incompatible

10%

12.5 mL

Ampicillin Sodium

Incompatible

10%

50 mg/mL

Tetracycline HCl

Incompatible

10%

12.5 mg/mL

BRONCHODILATORS

Isoproterenol HCl2

Compatible

3%

0.5%

Isoproterenol HCl2

Compatible

10%

0.05%

Isoproterenol HCl2

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)

.33% (1 part)

CONTRAST MEDIA

Iodized Oil

Incompatible

20%/20 mL

40%/10 mL

DECONGESTANTS

Phenylephrine HCl2

Compatible

3%

.25%

Phenylephrine HCl

Compatible

13.3% (2 parts)

.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 Phosphate5

Compatible

16.7%

3.3 mg/mL

OTHER AGENTS

Hydrogen Peroxide

Incompatible

(All ratios)

Sodium Bicarbonate

Compatible

20% (1 part)

4.2% (1 part)

Acetylcysteine As An Antidote For Acetaminophen Overdose


DOSAGE AND ADMINISTRATION

General

Regardless of the quantity of acetaminophen reported to have been ingested, administer acetylcysteine immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen. Do not await results of assays for acetaminophen level before initiating treatment with acetylcysteine. The following procedures are recommended:

1.
The stomach should be emptied promptly by lavage or by inducing emesis with syrup of ipecac. Syrup of ipecac should be given in a dose of 15 mL for children up to age 12, and 30 mL for adolescents and adults followed immediately by drinking copious amounts of water. The dose should be repeated if emesis does not occur in 20 minutes.
2.
In the case of a mixed drug overdose activated charcoal may be indicated. However, if activated charcoal has been administered, lavage before administering acetylcysteine treatment. Activated charcoal adsorbs acetylcysteine in vitro and may do so in patients and thereby may reduce its effectiveness.
3.
Draw blood for predetoxification acetaminophen plasma assay and for baseline SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes.
4.
Administer the loading dose of acetylcysteine, 140 mg per kg of body weight. (Prepare acetylcysteine for oral administration as described in the Specific Dosage Guide and Preparation table.)
5.
Determine subsequent action based on predetoxification plasma acetaminophen information. Choose ONE of the following four courses of therapy.
A.
Predetoxification plasma acetaminophen level is clearly in the toxic range (See Acetaminophen Assays - Interpretation and Methodology below):
Administer a first maintenance dose (70 mg/kg acetylcysteine) 4 hours after the loading dose. The maintenence 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.
B.
Predetoxification acetaminophen level could not be obtained:
Proceed as in A.
C.
Predetoxification acetaminophen level is clearly in the nontoxic range (beneath the dashed line on the nomogram) and you know that acetaminophen overdose occured at least 4 hours before the predetoxification acetaminophen plasma assays:
Discontinue administration of acetylcysteine.
D.
Predetoxification acetaminophen level was in the non-toxic range, but time of ingestion was unknown or less than 4 hours.
Because the level of acetaminophen at the time of the predetoxification assay may not be a peak value (peak may not be achieved before 4 hours post-ingestion), obtain a second plasma level in order to decide whether or not the full 17-dose detoxification treatment is necessary.
6.
If the patient vomits any oral dose within 1 hour of administration, repeat that dose.
7.
In the occasional instances where the patient is persistently unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation.
8.
Repeat SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes daily if the acetaminophen plasma level is in the potentially toxic range as discussed below.

Preparation of Acetylcysteine For Oral Administration — Oral administration requires dilution of the 20% solution with diet cola, or other diet soft drinks, to a final concentration of 5% (see Dosage Guide and Preparation table). If administered via gastric tube or Miller-Abbott tube, water may be used as the diluent. The dilutions should be freshly prepared and utilized within one hour. Remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours.

ACETYLCYSTEINE IS NOT APPROVED FOR PARENTERAL INJECTION.

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 FOUR 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.

Interpretation of Acetaminophen Assays:

1.
When results of the plasma acetaminophen assay are available refer to the nomogram below to determine if plasma concentration is in the potentially toxic range. Values above the solid line connecting 200 mcg/mL at 4 hours with 50 mcg/mL at 12 hours are associated with a possibility of hepatic toxicity if an antidote is not administered (do not wait for assay results to begin acetylcysteine treatment).
2.
If the predetoxification plasma level is above the broken line continue with maintenance doses of acetylcysteine. It is better to err on the safe side and thus the broken line is placed 25% below the solid line which defines possible toxicity.
3.
If the predetoxification plasma level is below the broken line described above, there is minimal risk of hepatic toxicity and acetylcysteine treatment can be discontinued.

Acetaminophen Assay Methodology:

Assay procedures most suitable for determining acetaminophen concentrations utilize high pressure liquid chromatography (HPLC) or gas liquid chromatography (GLC). The assay should measure only parent acetaminophen and not conjugated. The assay procedures listed below fulfill this requirement:

Selected techniques (non-inclusive)

HPLC:

1. Blair, D and Rumack, BH, Clin Chem. 1977; 23(4):743−745.
2. Howie, D, Andriaenssens, Pl, Prescott, LF. J Pharm Pharmacol 1977; 29(4):235−237.

GLC:

3. Prescott, LF. J Pharm Pharmacol 1971; 23(10);807−808.

Colorimetric:

4. Glynn, JP and Kendal, SE. Lancet 1975; 1(May 17):1147-1148.

SUPPORTIVE TREATMENT OF ACETAMINOPHEN OVERDOSE

1.
Maintain fluid and electrolyte balance based on clinical evaluation of state of hydration and serum electrolytes.
2.
Treat as necessary for hypoglycemia.
3.
Administer vitamin K1 if prothrombin time ratio exceeds 1.5 or fresh frozen plasma if the prothrombin time ratio exceeds 3.0.
4.
Diuretics and forced diuresis should be avoided (See table on preceding page).
DOSAGE GUIDE AND PREPARATION
**If patient weighs less than 20 kg (usually patients younger than 6 years), calculate the doses of Acetylcysteine Solution. Each mL of 20% Acetylcysteine Solution, contains 200 mg of acetylcysteine. The loading dose is 140 mg per kilogram of body weight. The maintenance dose is 70 mg/kg. Three (3) mL of diluent are added to each mL of 20% Acetylcysteine Solution. Do not decrease the proportion of diluent.

Doses in relation to body weight are:

Loading Dose of Acetylcysteine**

Grams

mL of 20%

mL of

Total mL of

Body Weight

Acetylcysteine

Acetylcysteine

Diluent

5% Solution

      (kg)

   (lb)

100−109

220 −240

15

75

225

300

90 − 99

198 −218

14

70

210

280

80 − 89

176 −196

13

65

195

260

70 − 79

154 −174

11

55

165

220

60 − 69

132 −152

10

50

150

200

50 − 59

110 −130

8

40

120

160

40 − 49

88 −108

7

35

105

140

30 − 39

66 − 86

6

30

90

120

20 − 29

44 − 64

4

20

60

80

Maintenance Dose**

(kg)

(lb)

100−109

220 −240

7.5

37

113

150

90 − 99

198 −218

7

35

105

140

80 − 89

176 −196

6.5

33

97

130

70 − 79

154 −174

5.5

28

82

110

60 − 69

132 −152

5

25

75

100

50 − 59

110 −130

4

20

60

80

40 − 49

88 −108

3.5

18

52

70

30 − 39

66 − 86

3

15

45

60

20 − 29

44 − 64

2

10

30

40

Estimating Potential for Hepatotoxicity:

The following nomogram has been developed to estimate the probability that plasma levels in relation to intervals post ingestion will result in hepatotoxicity.

chart plasma or serum acetaminophen concentration v time post-acetaminophen ingestion

Adapted from Rumack and Matthews, Pediatrics 1975; 55:871−876.

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