Mucolytic

Antidote for Acetaminophen Poisoning

Sandoz Canada Inc. Date of Preparation: October 21, 2005

, Jules-Leger Street Date of revision: Boucherville, QC, Canada

J4B 7K8

Control No.: 101433

- 1 -

PRODUCT MONOGRAPH ACETYLCYSTEINE SOLUTION

(Sandoz Standard) 200 mg/mL

ACTIONS AND 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 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. 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 parent compound, which is non-toxic, is extensively metabolized in the liver to form principally the sulfate and glucuronide conjugates which are also non-toxic and are rapidly excreted in the urine. A small fraction of the 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 non-toxic cysteine and mercapturic acid derivatives which are then excreted by the kidney. Therapeutic doses of acetaminophen do not saturate the glucuronide and sulfate conjugation pathways and do not result in formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose (150 mg/kg or greater) the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the P-450 pathway. 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 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.

CONTRAINDICATIONS

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

is contraindicated in those patients who are sensitive or who have developed a sensitivity to acetylcysteine. There are no contraindications to oral or intravenous administration of acetylcysteine in the treatment of acetaminophen overdose.

WARNINGS

After proper administration of acetylcysteine, an increased volume of liquefied bronchial secretions may occur. When cough is inadequate, the open airway must be maintained by mechanical suction if necessary. When there is a large mechanical block due to foreign body or local accumulation, the airway should be cleared by endotracheal aspiration, with or without bronchoscopy.

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

Asthmatics under treatment with

should be watched carefully. If bronchospasm progresses, this medication should be immediately discontinued.

Generalized urticaria has been observed rarely in patients receiving oral acetylcysteine for acetaminophen overdose. If this occurs and other allergic symptoms appear, treatment with acetylcysteine should be discontinued unless it is deemed essential and the allergic symptoms cannot be otherwise controlled. If encephalopathy due to hepatic failure is evident, acetylcysteine treatment should be discontinued to avoid further administration of nitrogenous substances. There is no data indicating acetylcysteine adversely influences hepatic failure; however, this remains a theoretical possibility.

PRECAUTIONS

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

With the administration of

as a mucolytic agent, the patient may initially notice a slight disagreeable odor which soon is not noticeable. With a face mask, there may be a stickiness on the face after nebulization which is easily removed by washing with water.

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD) ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

is not compatible with rubber and metals, particularly iron, copper and nickel. Silicone and lacquered rubber and plastic are satisfactory for use with

.

Under certain conditions, a color change may take place in the solution of acetylcysteine in the opened vial. The light purple color is the result of a chemical reaction which does not significantly impair the safety or mucolytic efficacy of acetylcysteine. Continued nebulization of an 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 Sterile Water for Injection USP, as concentration occurs, will obviate this problem. Occasionally severe and persistent vomiting occurs as a symptom of acute acetaminophen overdose. Treatment with oral acetylcysteine may aggravate the vomiting. Patients at risk of gastric hemorrhage (eg., 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 given accordingly. Dilution of the acetylcysteine with cola drinks minimizes the propensity of oral acetylcysteine to aggravate vomiting.

DRUG/LABORATORY INTERACTIONS

N-acetylcysteine may cause a false-positive reaction with reagent dipstick tests for urinary ketones.

DOSAGE AND ADMINISTRATION

DOSAGE AND ADMINISTRATION AS A MUCOLYTIC AGENT

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

is a 20% solution which may be diluted to a lesser concentration with either Sterile Sodium Chloride or Sterile Water for Injection USP.

Nebulization - face mask, mouth piece, tracheostomy:

When nebulized into a face mask, mouth piece or tracheostomy, 1-10 mL of the 20% solution may be given every 2- 6 hours; the recommended dose for most patients is 3-5 mL of the 20% solution 3-4 times daily.

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 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, 1-2 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% solution every 1 to 4 hours may 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 should be given by nebulization or by instillation intratracheally, prior to the procedure.

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

is usually administered as fine nebulae for its local effect, and the nebulizer used should be capable of providing optimal quantities of a suitable range of particle sizes.

Administration of aerosol: ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

may be administered using conventional nebulizers made of plastic or glass. Certain materials

used in nebulization equipment react with acetylcysteine. The most reactive are metals (notably iron and copper), and rubber. Where materials may come into contact with acetylcysteine solution, parts made of glass or plastic should be used. 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; 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.

STORAGE OF OPENED VIALS: If only a portion of the solution in the vial is used, then to minimize contamination, the remainder should be stored in a refrigerator and used within 96 hours.

Compatibility:

Acetylcysteine is incompatible with iodized oil (Lipiodol).

Antibiotics found to be incompatible when mixed in solution with acetylcysteine include tetracycline hydrochloride, oxytetracycline hydrochloride, erythromycin lactobionate and oleandomycin. These agents may be administered by nebulization from separate solutions if necessary.

DOSAGE AND ADMINISTRATION AS AN ANTIDOTE FOR ACETAMINOPHEN POISONING

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD) ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

In the case of an overdosage of acetaminophen,

should be administered immediately within 24 hours. To be effective in protecting against severe liver damage, therapy with

must be started within 10 hours of acetaminophen ingestion. There is some evidence of progressively diminished efficacy thereafter and treatment beyond 24 hours post-ingestion of acetaminophen is usually ineffective.

It should be borne in mind that after a fatal dose of acetaminophen, the patient may appear relatively well initially and may even continue normal activities for a day or two before the onset of hepatic failure. The following procedure is 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 to 30 mL for children and

30 to 45 mL for adults accompanied by drinking copious quantities of water. The dose should be repeated if emesis does not occur in 20 minutes. In the case of a mixed drug overdose activated charcoal may be indicated. However, if activated charcoal has been administered, perform gastric lavage before administering oral acetylcysteine treatment. Activated charcoal will absorb acetylcysteine and reduce its effectiveness. Draw blood for acetaminophen plasma assay and for baseline SGOT (AST), SGPT (ALT), bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes. The acetaminophen assay provides a reliable prognostic indication of potential hepatotoxicity and serves as a basis for determining the need for continuing with the maintenance doses of acetylcysteine treatment. (See section on acetaminophen assays - interpretation and methodology). The laboratory measurements are used to monitor hepatic and renal function and electrolyte fluid balance. Administer the loading dose of acetylcysteine as outlined in Table I or II according to route of administration employed. For information regarding oral and intravenous maintenance doses, see Tables I and II. If the patient vomits the oral loading dose or any oral maintenance dose within 1 hour of administration, repeat that dose. If the patient is unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation or by the intravenous route. Repeat SGOT (AST), SGPT (ALT), bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes daily if acetaminophen plasma level is in the potentially toxic range as discussed below.

PREPARATION OF ACETYLCYSTEINE SOLUTION FOR ORAL ADMINISTRATION

Oral administration requires dilution of the 20% solution with cola drinks, or other soft drinks, to a final concentration of 5% (See Table I). 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 1 hour. Remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours.

PREPARATION OF ACETYLCYSTEINE SOLUTION FOR INTRAVENOUS ADMINISTRATION

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD) ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

may be used for intravenous administration following acetaminophen overdose according to the Dosage Guidelines in Table II. Dilutions recommended should be prepared with 5% Dextrose Injection USP, as appropriate.

for intravenous use should be considered as a single-use container. Solutions recommended under each column in Table II should be freshly prepared and used only over times stated.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration whenever solution and container permit. Solution showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portions.

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. DO NOT WAIT FOR ASSAY RESULTS TO BEGIN ACETYLCYSTEINE TREATMENT. For any given dose of acetaminophen, a greater formation of toxic metabolite may occur if there is a history of chronic alcohol ingestion and/or concomitant barbiturate therapy. This should be kept in mind when therapy is based on acetaminophen blood levels interpretation of acetaminophen assays: (Refer to nomogram, Figure 1).

1. When results of the plasma acetaminophen assay are available refer to nomogram (Figure 1) to determine if plasma concentration is in the potentially toxic range. Values above the solid line connecting 200 ug/mL at 4 hours with 50 ug/mL at 12 hours are associated with a possibility of hepatic toxicity if an antidote is not administered.

2. If the 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 plotted 25% below the solid line which defines possible toxicity.

3. If the plasma level is below the broken line described above, there is minimal risk of hepatic toxicity and acetylcysteine treatment can be discontinued.

When discontinuation of treatment with acetylcysteine is contemplated, the possibility of chronic alcohol ingestion and/or concomitant barbiturate therapy should be kept in mind, since under these circumstances blood levels of the parent compound may underestimate the true risk of hepatotoxicity. Suitable assay procedures for measuring acetaminophen levels in plasma are listed below. These methods detect only parent acetaminophen and not conjugated. HPLC:

1. Blair, D., and Rumack, B.H., Clin. Chem. 23 (4) : 743-745 (April) 1977.

2. Howie, D., Adriaenssens, P.I., and Prescott, L.F.: Journ. Pharm. And Pharmacol. : 29(4) : 235-237 (April) 1977.

GLC: Prescott, L.F., Journ. Pharm. And Pharmacol. : 23(10) : 807-808 (Oct.) 1971. Colorimetric:

Glynn, J.P., and Kendal, S.E. : The Lancet 1, 1147-1148 (May 17) 1975.

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.

Hemodialysis or peritoneal dialysis have not been found helpful.

TABLE I: DOSAGE GUIDE AND PREPARATION FOR ORAL ADMINISTRATION Doses in relation to body weight are:

Four hours after the loading dose, administer the first maintenance dose (70 mg of acetylcysteine/kg of body weight). The maintenance dose is then repeated at 4 hour intervals for a total of 17 doses unless the acetaminophen assay reveals a non-toxic level as discussed above.

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

* * If patient weighs less than 20 kg, usually patients younger than 6 years, calculate the dose of

. Each mL of 20 %

contains 200 mg of

acetylcysteine. The loading dose is 140 mg/kg of body weight. The maintenance dose is 70 mg/kg. Three (3) mL of diluent are added to each mL of 20%

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

. Do not decrease the

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD)

proportion of diluent. Increased gastrointestinal irritation is associated with increased concentrations of

.

TABLE II: DOSAGE GUIDE AND PREPARATION FOR INTRAVENOUS ADMINISTRATION

The volumes and rates of infusion for children suggested above must be adjusted according to the medical circumstances and restrictions in the volumes of parenteral fluids administered as they apply to each individual patient.

E

STIMATING POTENTIAL FOR HEPATOTOXICITY

A nomogram, Figure 1, has been developed to estimate the probability that plasma levels in relation to intervals post-ingestion will result in hepatotoxicity.

PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper Name: ACETYLCYSTEINE

Chemical Name:

N-Acetyl-L-Cysteine

Structural Formula:

Molecular Formula: C5H9NO3S

O

HS OH

N CH3

H

O

Molecular Weight:

163.2

Description:

White crystalline powder or colourless crystals. Freely

soluble in water and alcohol, and practically insoluble in methylene chloride.

Melting Range:

104-110degC.

pH:

2.0 - 2.8 (1% aqueous solution).

COMPOSITION

Each mL contains acetylcysteine 200 mg, disodium edetate 0.5 mg, sodium hydroxide to adjust pH and water for injection.

STABILITY AND STORAGE RECOMMENDATIONS

STORAGE OF UNOPENED VIALS Store unopened vials between 15 and 30degC. Protect from light. Under certain conditions, a color change may take place in the solution of acetylcysteine in the opened vial. The light purple color is the result of a chemical reaction which does not significantly impair the safety or mucolytic efficacy of acetylcysteine.

STORAGE OF OPENED VIALS

Acetylcysteine Solution for Inhalation:

Store opened vials in the refrigerator between 2 and 8degC and use within 96 hours. If an admixture is prepared use immediately (see DOSAGE AND ADMINISTRATION: AS A MUCOLYTIC AGENT).

STORAGE OF DILUTED SOLUTION FOR IV AND/OR ORAL/INHALATION SOLUTION

Diluted Solutions:

Acetylcysteine Solution for Oral Administration:

Dilute the 20% solution in cola drinks or other soft drinks to a concentration of 5% (see DOSAGE AND ADMINISTRATION - PREPARATION OF ACETYLCYSTEINE SOLUTION FOR

ORAL ADMINISTRATION). 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 Solution for Intravenous Infusion:

Dilutions should be prepared with 5% Dextrose Injection USP. Discard unused portion. Solutions should be freshly prepared and used only over times stated. (see DOSAGE AND ADMINISTRATION PREPARATION OF SOLUTION FOR INTRAVENOUS SOLUTIONS)

Acetylcysteine is not compatible with rubber and metals, particularly iron, copper and nickel.

AVAILABILITY OF DOSAGE FORMS

ACETYLCYSTEINE SOLUTION (SANDOZ STANDARD) Store between 15 and 30degC. Protect from light.

20% is available in lacquered rubber stoppered glass vials of 10 mL and 30 mL, boxes of 1.

PHARMACOLOGY

Acetylcysteine is highly efficacious in preventing lethality from acute acetaminophen overdosage in CF-1 mice, even when therapy is delayed 41/2 hours after dosing with acetaminophen. This time frame is especially noteworthy, since unprotected mice become debilitated by 11/2 hours, have liver involvement by 31/2 hours and die as early as 4 to 5 hours post-overdose. - 14 - The protective effect of acetylcysteine in preventing lethality was accompanied by marked hepatoprotection, which was closely reflected by the serum transaminase profile (SGPT) when the antidote was administered early. However, SGPT levels were found to be poor prognostic indicators of survival in late acetylcysteine administration. Parallel comparisons with reference compounds indicate that acetylcysteine is more efficacious than cysteamine in both overall survival rate and effectiveness on late administration (41/2 hours after acetaminophen dosing). Similar studies with methionine indicate that both acetylcysteine and methionine show high efficacy, but that methionine produces a bell-shaped rather than a linear dose response pattern on late administration, i.e., the higher as well as the lower doses resulted in lower survival rates that the mid- range doses. A highly lethal acetaminophen challenge dose was used (1500 mg/kg) resulting in a 7% survival rate in the untreated mice. The effects of delayed administration after a less severe challenge (1200 mg/kg) were examined. The survival rate in the untreated mice was 70%. Treatment was initiated 9 hours after overdosing. When acetylcysteine was administered at this time which coincided with peak acetaminophen-induced liver insult, slight protection rather than- exacerbation of toxicity occurred. In this experiment the reference compound, methionine, showed a similar pattern. Cysteamine, in contrast, showed a tendency to worsen the overall condition of animals if treatment was instituted as early as 41/2 hours after dosing with 1200 mg/kg of acetaminophen. Safety assessment of acutely administered acetylcysteine to normal CF-1 mice indicates that it is extremely well tolerated by both oral and intravenous routes.

TOXICOLOGY

Acute toxicity studies conducted in various animal species show that acetylcysteine is innocuous. The oral LD50 of acetylcysteine was greater than 1000 mg/kg in dogs, greater than 3000 mg/kg in mice and 6000 mg/kg in rats. With parenteral administration (intravenous or intraperitoneal) to the same three species and to guinea pigs, the LD50 ranged between 700 mg/kg for the dog and 2650 mg/kg for the rat. Gross and microscopic studies performed at autopsy on rats and dogs, treated with very large oral doses of acetylcysteine for 8 weeks, revealed no pathologic abnormalities in either species attributable to the administration of the agent. During administration of the test doses, growth and body weights of the animals were not deleteriously affected. Hemograms and liver function studies revealed no abnormalities attributable to the drug. Histologic studies were done in guinea pigs exposed to aerosol sprays of 3% and 18% solutions of acetylcysteine for 15 minutes daily for 8 weeks. The histologic sections of the lungs, trachea, bronchi and larynx of these animals were not different from those of the control group exposed to normal saline. The mortality and morbidity rates in the two groups were not significantly different. - 15 - Other groups of guinea pigs were exposed to nebulization of the 3% and 18% solutions of acetylcysteine daily for three weeks, rested for two weeks, and then re-exposed for three days. These studies revealed no evidence of sensitization. Dogs, rabbits and rats were exposed to a chamber atmosphere produced by 30 second nebulization of a 20% solution of acetylcysteine; these test animals remained in the atmosphere for an additional 15 minutes. Exposure was done twice daily for 35 consecutive days. Other groups of rabbits, rats and guinea pigs were exposed to a chamber atmosphere produced by continuous nebulization of a 20% solution of acetylcysteine for 1 hour a day 5 days a week for 12 weeks. No clinical or histopathological changes were found that could be attributed to acetylcysteine. No evidence of local irritation was observed with acetylcysteine injected intracutaneously in guinea pigs. Ciliary activity in excised rat trachea was not inhibited by topical application of acetylcysteine. Toxicology mechanism studies indicated that the antidotal profile of acetylcysteine is not related to facilitated plasma or urinary clearance of acetaminophen or acetaminophen metabolites, nor to cleavage of covalent bonds or significant tissue re-distribution of acetaminophen or its metabolites. Acetylcysteine antidotal therapy was associated with increased mercapturate conjugate in the urine, suggesting that acetylcysteine, like endogenous glutathione, may be serving as a substrate for the detoxification of the reactive metabolite of acetaminophen.