ACETYLCYSTEINE: 2,411 Adverse Event Reports & Safety Profile

Acetylcysteine injection is an intravenous antidote for the treatment of acetaminophen overdose. Acetylcysteine is the nonproprietary name for the N-acetyl derivative of the naturally occurring amino acid, L-cysteine (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 molecular formula of the compound is C 5 H 9 NO 3 S, and its molecular weight is 163.2. Acetylcysteine has the following structural formula: Acetylcysteine injection is supplied as a sterile solution in vials containing 20% w/v (200 mg/mL) acetylcysteine USP. The pH of the solution ranges from 6 to 7.5. Acetylcysteine injection contains the following inactive ingredients: 0.5 mg/mL edetate disodium, sodium hydroxide (used for pH adjustment), and Water for Injection, USP. The amount of sodium in acetylcysteine injection is approximately 30 mg/mL. Because acetylcysteine injection is administered based on a patient’s weight, the amount of sodium administered in a course of treatment will vary from approximately 225 mg to 4,500 mg. The use of ½ normal saline will contribute approximately an additional 1,770 mg of sodium per liter of diluent.

Acetylcysteine Chemical

Structure

AND USAGE Acetylcysteine Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen. Overdose incidences are divided into two types; Acute Ingestion or Repeated Supratherapeutic Ingestion (RSI). [see Dosage and Administration ( 2 ) and Acetaminophen Assays – Interpretation and Methodology -(Acute or Repeated Supratherapeutic Ingestion) ( 1.1 , 1.2 )] . On admission for suspected acetaminophen overdose, a serum blood sample should be drawn at least 4 hours after ingestion to determine the acetaminophen level and will serve as a basis for determining the need for treatment with acetylcysteine. If the patient presents after 4 hours post-ingestion, the serum acetaminophen sample should be determined immediately.

Acetylcysteine

Injection should be administered within 8 hours from acetaminophen ingestion for maximal protection against hepatic injury for patients whose serum acetaminophen levels fall above the "possible" toxicity line on the Rumack-Matthew nomogram (line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours); [see Acetaminophen Assays – Interpretation and Methodology (1.1, 1.2 )] . If the time of ingestion is unknown, or the serum acetaminophen level is not available, cannot be interpreted, or is not available within the 8 hour time interval from acetaminophen ingestion, Acetylcysteine Injection should be administered immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen, regardless of the quantity reported to have been ingested. The aspartate aminotransferase (AST, SGOT), alanine aminotranferase (ALT, SGPT), bilirubin, prothrombin time, creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes also should be determined in order to monitor hepatic and renal function and electrolyte and fluid balance. NOTE: The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between 0 to 8 hours. Efficacy diminishes progressively after 8 hours and treatment initiation between 15 and 24 hours post-ingestion of acetaminophen yields limited efficacy. However, it does not appear to worsen the condition of patients and it should not be withheld, since the reported time of ingestion may not be correct.

Acetylcysteine

Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen (1)

1.1 Acetaminophen Assays Interpretation and Methodology – Acute Ingestion 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 When results of the plasma acetaminophen assay are available, refer to the nomogram in Figure 1 to determine if plasma concentration is in the potentially toxic range. Values above the line connecting 200 mcg/mL at 4 hours with 50 mcg/mL at 12 hours (probable line) are associated with a probability of hepatic toxicity if an antidote is not administered. If the predetoxification plasma level is above the line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours (possible line), continue with maintenance doses of acetylcysteine. It is better to err on the safe side and thus this line, defining possible toxicity, is plotted 25% below the line defining probable toxicity. If the predetoxification plasma level is below the line connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at 12 hours (possible line), there is minimal risk of hepatic toxicity, and Acetylcysteine treatment may be discontinued.

Estimating

Potential for Hepatotoxicity: The following depiction of the Rumack- Matthew nomogram has been developed to estimate the probability that plasma levels in relation to intervals post-ingestion will result in hepatotoxicity.

The

Rumack-Matthew nomogram may underestimate the risk for hepatotoxicity in some patients with risk factors such as chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid).

Figure

1. Rumack-Matthew Nomogram: Figure 1. Michael J Hodgman, Alexander R Garrard, A Review of Acetaminophen Poisoning.

Crit Care

Clin . 28 (2012) 499-516. Stephen J. Wolf, Kennon Heard, et.al, Clinical Policy: Critical Issues in the Management of Patients Presenting to the Emergency Department with Acetaminophen Overdose.

Ann Emerg

Med . 2007:50:292-313. figure 1

1.2 Acetaminophen Assays Interpretation and Methodology – Repeated Supratherapeutic Ingestion Repeated Supratherapeutic Ingestion (RSI) is defined as ingestion of acetaminophen at doses higher than those recommended for extended periods of time. The nomogram does not apply to patients with RSI. Treatment is based on the acetaminophen and elevated AST/ALT levels indicative of potential toxicity due to acetaminophen. For specific treatment information regarding the clinical management of repeated supratherapeutic acetaminophen overdose, please contact your regional poison center at 1-800-222-1222, or alternatively, a special health professional assistance line for acetaminophen overdose at 1-800-525-6115.

Figure

2.

Acetylcysteine Injection Treatment Flow Chart

1 Acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. 2 With an extended-release preparation, an acetaminophen level drawn less than 8 hours post-ingestion may be misleading. Draw a second level at 4 to 6 hours after the initial level. If either falls above the toxicity line, acetylcysteine treatment should be initiated. 3 Acetylcysteine may be withheld until acetaminophen assay results are available as long as initiation of treatment is not delayed beyond 8 hours post-ingestion. If more than 8 hours post-ingestion, start acetylcysteine treatment immediately. figure 2

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. 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 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. IN VITRO COMPATIBILITY 1 TESTS OF ACETYLCYSTEINE SOLUTION RATIO TESTED 6 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)

Bacitracin

2,3 (mix and use at once)

Compatible

10% 5,000 U/mL Chloramphenicol Sodium Succinate Compatible 20% 20 mg/mL Carbenicillin Disodium 2 (mix and use at once)

Compatible

10% 125 mg/mL Gentamicin Sulfate 2 Compatible 10% 20 mg/mL Kanamycin Sulfate 2 (mix and use at once)

Compatible

10% 167 mg/mL Compatible 17% 85 mg/mL Lincomycin HCl 2 Compatible 10% 150 mg/mL Neomycin Sulfate 2 Compatible 10% 100 mg/mL Novobiocin Sodium 2 Compatible 10% 25 mg/mL Penicillin G Potassium 2 Compatible 10% 25,000 U/mL (mix and use at once)

Compatible

10% 100,000 U/mL Polymyxin B Sulfate 2 Compatible 10% 50,000 U/mL Cephalothin Sodium Compatible 10% 110 mg/mL Colistimethate Sodium 2 (mix and use at once)

Compatible

10% 37.5 mg/mL Vancomycin HCl 2 Compatible 10% 25 mg/mL Amphotericin B Incompatible 4%-15% 1.0-4.0 mg/mL Chlortetracycline HCl 2 Incompatible 10% 12.5 mg/mL Erythromycin Lactobionate Incompatible 10% 15 mg/mL Oxytetracycline HCl Incompatible 10% 12.5 mg/mL Ampicillin Sodium Incompatible 10% 50 mg/mL Tetracycline HCl Incompatible 10% 12.5 mg/mL BRONCHODILATORS Isoproterenol HCl2 Compatible 3.0% 0.5% Isoproterenol HCl 2 Compatible 10% 0.05% Isoproterenol HCl 2 Compatible 20% 0.05% Isoproterenol HCl Compatible 13.3% (2 parts) .33% (1 part) Isoetharine HCl Compatible 13.3% .33% (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 HCl 2 Compatible 3.0% .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 Phosphate 5 Compatible 16.7% 3.3 mg/mL OTHER AGENTS Hydrogen Peroxide Incompatible (All ratios)

Sodium Bicarbonate Compatible

20% (1 part) 4.2% (1 part) 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 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. Therapeutic doses of acetaminophen do not saturate the glucuronide and sulfate conjugation pathways and do not result in the 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 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. Rash with or without mild fever has been observed rarely. DOSAGE & ADMINISTRATION General Regardless of the quantity of acetaminophen reported to have been ingested, administer acetylcysteine (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 solution. 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 quantities 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 solution treatment. Activated charcoal adsorbs acetylcysteine solution in vitro and may do so in patients and thereby may reduce its effectiveness. 3. Draw blood for predetoxification acetaminophen plasma assay and 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. 1. 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 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. 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 solution, 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 Solution 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 SOLUTION 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 4 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 µg/mL at 4 hours with 50 µg/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 solution. 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 solution 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 (NONINCLUSIVE) HPLC: GLC Colorimetric Supportive Treatment of Acetaminophen Overdose DOSAGE GUIDE AND PREPARATION Doses in relation to body weight are: Loading Dose of Acetylcysteine Solution ** Body Weight grams Acetylcysteine mL of 20% Acetylcysteine mL of Diluent Total mL of 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 ** If patient weighs less than 20 kg (usually patients younger than 6 years), calculate the dose of acetylcysteine solution. Each mL of 20% acetylcysteine 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. Do not decrease the proportion of diluent.

Estimating

Potential for Hepatoxicity The following nomogram has been developed to estimate the probability that plasma levels in relation to intervals post ingestion will result in hepatoxocity. Adapted from Rumack and Matthews, Pediatrics 1975; 55: 871-876. Image

Contraindications: This product is contraindicated in patients with a known hypersensitivity to any of the ingredients. Folcyteine™ is contraindicated in patients with hypercalcemia, malabsorption syndrome, abnormal sensitivity to the toxic effects of vitamin D, and hypervitaminosis D.

REACTIONS Most common adverse reactions (> 2%) are rash, urticaria/facial flushing and pruritus ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Studies Experience The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>

Fluid

Overload [see Warnings and Precautions ( 5.2 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the literature, the most frequently reported adverse reactions attributed to intravenous acetylcysteine administration were rash, urticaria and pruritus. The frequency of adverse reactions has been reported to be between 0.2% and 21%, and they most commonly occur during the initial loading dose of acetylcysteine.

Loading Dose/Infusion

Rate Study In a randomized, open-label, multi-center clinical study conducted in Australia in patients with acetaminophen poisoning, the rates of hypersensitivity reactions between a 15-minute and 60-minute intravenous infusion for the 150 mg/kg loading dose of acetylcysteine were compared. The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration is presented in Table 4 . Overall, 17% of patients developed an acute hypersensitivity reaction (18% in the 15-minute infusion group; 14% in the 60-minute infusion group) [see Warnings and Precautions ( 5.1 ), Clinical Studies ( 14 )] .

Table

4. Incidence of Drug-Related Adverse Reactions Occurring Within the First 2 Hours Following Study Drug Administration by Preferred Term: Loading Dose/Infusion Rate Study Treatment Group 15-minutes 60-minutes Unkn= Unknown; NOS= not otherwise specified Number of Patients n=109 n=71 Cardiac disorders 5 (5%) 2 (3%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Tachycardia NOS 4 (4%) 1 (1%) 2 (3%) Gastrointestinal disorders 16 (15%) 7 (10%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Nausea 1 (1%) 6 (6%) 1 (1%) 1 (1%) Vomiting NOS 2 (2%) 11 (10%) 2 (3%) 4 (6%)

Immune System Disorders

20 (18%) 10 (14%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Hypersensitivity reaction 2 (2%) 6 (6%) 11 (10%) 1 (1%) 4 (6%) 5 (7%) 1 (1%) Respiratory, thoracic and mediastinal disorders 2 (2%) 2 (3%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pharyngitis 1 (1%)

Rhinorrhea

1 (1%)

Rhonchi

1 (1%) Throat tightness 1 (1%) Skin & subcutaneous tissue disorders 6 (6%) 5 (7%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pruritus 1 (1%) 2 (3%) Rash NOS 3 (3%) 2 (2%) 3 (4%) Vascular disorders 2 (2%) 3 (4%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Flushing 1 (1%) 1 (1%) 2 (3%) 1 (1%)

Safety

Study A large multi-center study was performed in Canada where data were collected from patients who were treated with intravenous acetylcysteine for acetaminophen overdose between 1980 and 2005. This study evaluated 4709 adult cases and 1905 pediatric cases. The incidence of hypersensitivity reactions in adult (overall incidence 8%) and pediatric (overall incidence 10%) patients is presented in Table 5 and Table 6 .

Table

5. Distribution of reported hypersensitivity reactions in adult patients receiving intravenous acetylcysteine Reaction Incidence (%) n=4709 *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.

Urticaria/Facial

Flushing 6.1% Pruritus 4.3% Respiratory Symptoms* 1.9% Edema 1.6% Hypotension 0.1% Anaphylaxis 0.1% Table 6. Distribution of reported hypersensitivity reactions in pediatric patients receiving intravenous acetylcysteine Reaction Incidence (%) n=1905 *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.

Urticaria/Facial

Flushing 7.6% Pruritus 4.1% Respiratory Symptoms* 2.2% Edema 1.2% Anaphylaxis 0.2% Hypotension 0.1%

6.2 Postmarketing Experience Adverse Reactions from Observational Studies Observational studies from published literature have described rates of hypersensitivity reactions identified by retrospective chart review in subjects receiving the two-bag regimen after adoption of this regimen as institutional policy in three non-US settings and one US setting compared to a historical control group that received the three-bag regimen.

Table

7 displays the incidence of hypersensitivity reactions in patients who received two-bag or three-bag regimens of intravenous acetylcysteine admitted between 2009 to 2020.

Table

7. Incidence of Hypersensitivity Reactions in Patients who Received Two-bag or Three-bag Regimens of Intravenous Acetylcysteine in Published Literature Study Hypersensitivity Reactions in Patients Receiving Two-Bag Regimen Hypersensitivity Reactions in Patients Receiving Three-Bag Regimen Study 1 (Three Danish hospitals) 4% (19/507) 16% (47/292)

Study

2 (Four Australian hospitals) 5% (8/163) 14% (45/313)

Study

3 (Nine Australian hospitals) 1% (17/1300) 7% (65/911)

Study

4 (One US hospital) 19% (18/93) 23% (34/150)

Adverse

Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of ACETADOTE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: fatal anaphylaxis

AND PRECAUTIONS

• Hypersensitivity Reactions, Including Hypotension, Wheezing, Shortness of Breath and Bronchospasm: Observe patients during and after the infusion; immediately discontinue infusion if a serious reaction occurs and initiate appropriate treatment. Acetylcysteine injection infusion may be carefully restarted after treatment of hypersensitivity has been initiated ( 5.1 ).
• Fluid Overload: Total volume administered should be reduced for patients weighing less than 40 kg and for those requiring fluid restriction ( 5.2 ).

5.1 Hypersensitivity Reactions Serious acute hypersensitivity reactions during acetylcysteine administration including rash, hypotension, wheezing, and/or shortness of breath, have been observed in patients receiving intravenous acetylcysteine for acetaminophen overdose and occurred soon after initiation of the infusion [ see Adverse Reactions (6.1) ]. If a severe hypersensitivity reaction occurs, immediately stop the infusion of acetylcysteine injection and initiate appropriate treatment. One patient with asthma developed bronchospasm and died after intravenous administration of acetylcysteine. Acetylcysteine injection should be used with caution in patients with asthma, or where there is a history of bronchospasm. Patients with asthma should be closely monitored during initiation of acetylcysteine injection therapy and throughout acetylcysteine injection therapy. Acute flushing and erythema of the skin may occur in patients receiving acetylcysteine intravenously. These reactions usually occur 30 to 60 minutes after initiating the infusion and often resolve spontaneously despite continued infusion of acetylcysteine. If a reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as a hypersensitivity reaction. Management of less severe hypersensitivity reactions should be based upon the severity of the reaction and include temporary interruption of the infusion and/or administration of antihistaminic drugs. The acetylcysteine injection infusion may be carefully restarted after treatment of the hypersensitivity symptoms has been initiated; however, if the hypersensitivity reaction returns upon re-initiation of treatment or increases in severity, acetylcysteine injection should be discontinued and alternative patient management should be considered.

5.2 Fluid Overload The total volume of acetylcysteine injection administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. To avoid fluid overload, the volume of diluent should be reduced as needed [ see Dosage and Administration (2) ]. If volume is not adjusted fluid overload can occur, potentially resulting in hyponatremia, seizure and death. Intravenous administration of acetylcysteine injection can cause fluid overload, potentially resulting in hyponatremia, seizure and death. To avoid fluid overload, use the recommended dilution shown in Tables 2, 3 and 4 [ see Dosage and Administration (2.4) ].

PRECAUTIONS General With the administration of acetylcysteine solution, 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 solution in the opened bottle. The light purple color is the result of a chemical reaction which does not significantly affect safety or mucolytic effectiveness of acetylcysteine solution. 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, MUTAGENSIS, 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 data 1 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 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 6th 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 solution 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. Lactation 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 solution is administered to a nursing woman.

Precautions

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 (see Preparation of Acetylcysteine Solution for Oral Administration ) minimizes the propensity of oral acetylcysteine to aggravate vomiting.

INTERACTIONS No drug-drug interaction studies have been conducted. No drug-drug interaction studies have been conducted ( 7 )

Adrenalinum 9C, 15C, GCSF 4C, Interferon gamma 5C.......................Immune support Argentum nitricum 9C, Cortex cerebralis 4C, 7C....................................Relieves mild anxiety, restlessness Black horehound 3X, Citrus decumana 3X.............................................Drainage Glutathione 4C........................................................................................Antioxidant Kali carbonicum 9C, Lithium carbonicum 8X..........................................Relieves mild anxiety, restlessness Melatonin 4C, 15C, Stomach 7C............................................................Relieves mild anxiety, restlessness Nux vomica 5C, 7C, 9C, 15, Thalamus 7C.............................................Relieves mild anxiety, restlessness N-acetyl cysteine 4C...............................................................................Antiaging Penicillium notatum 8X, Sporobolomyces griseus 8X.............................Immune support Superior gastric plexus 7C......................................................................Relieves mild anxiety, restlessness

Inactive ingredient : Sucrose.