Acetylcysteine

Acetylcysteine - Acetadote ®

Usual Diluents

Additional comments: Acetadote is hyperosmolar (2600 mOsm/L) and is compatible with:

• 5% Dextrose (D5W),
• ½ NS (0.45% Sodium Chloride Injection), and
• Water for Injection (WFI).

Standard Dilutions   [Amount of drug] [Infusion volume] [Infusion rate]

Patients >20 - <40 kg (See comments below):
Loading Dose: 150 mg/kg in 100 mL of diluent administered over 60 min
Dose 2: 50 mg/kg in 250 mL of diluent administered over 4 hr
Dose 3: 100 mg/kg in 500 mL of diluent administered over 16 hr

Patients ≤20 kg (See comments below):
Loading Dose: 150 mg/kg in 3 mL/kg of body weight of diluent administered over 60 min
Dose 2: 50 mg/kg in 7 mL/kg of body weight of diluent administered over 4 hr
Dose 3: 100 mg/kg in 14 mL/kg of body weight of diluent administered over 16 hr

Stability / Miscellaneous

Stability data:

Stability Refrigerated:
Stability Room Temp:  Stability studies indicate that the diluted
solution is stable for 24 hours at controlled room temperature.
Store unopened vials at controlled room temperature, 20° to 25°C (68° to
77°F)
Reconstituted Vial/Powder: Solution

Notes:  Single dose vial,
preservative-free, discard unused portion. If vial was previously
opened, do not use for intravenous administration.

Note: The color of acetylcysteine injection may turn from essentially
colorless to a slight pink or purple once the stopper is punctured. The
color change does not affect the quality of the product

Stability: 24 hours room temp.
Supplied: Acetadote injection is available as a 20% solution in 30 ml (200mg/ml) single glass vials.

Do not use previously opened vials for IV administration.
See package insert for additional comments.

CLINICAL PHARMACOLOGY
Mechanism of action

Acetaminophen Overdose:
Acetaminophen is 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. It is extensively metabolized in the liver to form principally the sulfate and glucoronide conjugates which are excreted in the urine. A small fraction of an ingested dose is metabolized in the liver by isozyme CYP2E1 of the cytochrome P-450 mixed function oxidase enzyme system to form a reactive, potentially toxic, intermediate metabolite. The toxic metabolite preferentially conjugates with hepatic glutathione to form nontoxic cysteine and mercapturic acid derivatives, which are then excreted by the kidney. Recommended therapeutic doses of acetaminophen are not believed to saturate the glucuronide and sulfate conjugation pathways and therefore are not expected to result in the formation of sufficient reactive metabolite to deplete glutathione stores. However, following ingestion of a large overdose, the glucuronide and sulfate conjugation pathways are saturated resulting in a larger fraction of the drug being metabolized via the cytochrome P-450 pathway and therefore, the amount of acetaminophen metabolized to the reactive intermediate increases. The increased formation of the 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 I.V. Treatment:
Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. It is most effective when given early, with benefit seen principally in patients treated within 8-10 hours of the overdose. Acetylcysteine likely 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 AND USAGE
Acetadote, administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or lessen hepatic injury [see Dosage and Administration (2) and Acetaminophen Assays – Interpretation and Methodology (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.

Acetadote 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, Acetadote 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 – 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.

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

1. 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.
2. 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.
3. 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.

Figure 1. Rumack-Matthew Nomogram: Plasma or Serum Acetaminophen Concentration vs. Time Post Acetaminophen Ingestion (Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871-876 and Rumack BH, Peterson RC, Kock GG, Amara IA. Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment. Arch Intern Med. 1981;141:380-385).

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.

*Acetaminophen levels drawn less than 4 hours post-ingestion may be misleading.

# 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.

***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.

DOSAGE AND ADMINISTRATION
The total dose of Acetadote is 300 mg/kg administered over 21 hours. Please refer to the guidelines below for dose preparation based upon patient weight.

Administration Instructions (Three-Bag Method: Loading, Second and Third Dose)
Patients ≥40 kg (Table 1):

Loading Dose: 150 mg/kg  (maximum of 15 grams) in 200 mL of diluent administered over 60 min

Second Dose: 50 mg/kg  (maximum of 5 grams) in 500 mL of diluent administered over 4 hr

Third Dose: 100 mg/kg  (maximum of 10 grams) in 1000 mL of diluent administered over 16 hr

1. Acetadote is hyperosmolar (2600 mOsm/L) and is compatible with 5% Dextrose (D5W), ½ Normal Saline (0.45% Sodium Chloride Injection, ½ NS), and Water for Injection (WFI).

The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction:

Patients >20 - <40 kg (Table 2):

Loading Dose: 150 mg/kg in 100 mL of diluent¹ administered over 60 min

Second Dose: 50 mg/kg in 250 mL of diluent administered over 4 hr

Third Dose: 100 mg/kg in 500 mL of diluent administered over 16 hr

1. Acetadote is hyperosmolar (2600 mOsm/L) and is compatible with 5% Dextrose (D5W), ½ Normal Saline (0.45% Sodium Chloride Injection, ½ NS), and Water for Injection (WFI).

Patients ≤20 kg (Table 3): 

Loading Dose: 150mg/kg in 3mL/kg of body weight of diluent¹ administered over 60 min

Second Dose: 50mg/kg in 7mL/kg of body weight of diluent administered over 4 hr

Third Dose: 100mg/kg in 14mL/kg of body weight of diluent administered over 16 hr

1. Acetadote is hyperosmolar (2600 mOsm/L) and is compatible with 5% Dextrose (D5W), ½ Normal Saline (0.45% Sodium Chloride Injection, ½ NS), and Water for Injection (WFI).

Stability:
Single dose vial, preservative-free, discard unused portion. If vial was previously opened, do not use for I.V. administration.

Stability studies indicate that the diluted solution is stable for 24 hours at controlled room temperature.

Note: The color of Acetadote may turn from essentially colorless to a slight pink or purple once the stopper is punctured. The color change does not affect the quality of the product.

Renal Impairment
No data are available to determine if a dose adjustment in patients with moderate or severe renal impairment is required.

Hepatic Impairment
Although there was a threefold increase in acetylcysteine plasma concentrations in patients with hepatic cirrhosis, no data are available to determine if a dose adjustment in these patients is required. The published medical literature does not indicate that the dose of acetylcysteine in patients with hepatic impairment should be reduced.

DOSAGE FORMS AND STRENGTHS
Acetadote (acetylcysteine) Injection is available as a 20% solution (200mg/mL) in 30 mL single dose glass vials. Acetadote is sterile and can be used for I.V. administration.

CONTRAINDICATIONS
Acetadote is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine.

WARNINGS AND PRECAUTIONS

Anaphylactoid Reactions
Serious anaphylactoid reactions, including death in a patient with asthma, have been reported in patients administered acetylcysteine intravenously.

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. Anaphylactoid reactions (defined as the occurrence of an acute hypersensitivity reaction during acetylcysteine administration including rash, hypotension, wheezing, and/or shortness of breath) have been observed in patients receiving I.V. acetylcysteine for acetaminophen overdose and occurred soon after initiation of the infusion [see Adverse Reactions (6.1)]. If a reaction to acetylcysteine involves more than simply flushing and erythema of the skin, it should be treated as an anaphylactoid reaction. This usually entails administering antihistaminic drugs and in severe cases may require administration of epinephrine. In addition, the acetylcysteine infusion may be interrupted until treatment of the anaphylactoid symptoms has been initiated and then carefully restarted. If the anaphylactoid reaction returns upon reinitiation of treatment or increases in severity, intravenous acetylcysteine should be discontinued and alternative patient management should be considered.

Monitoring patients with asthma
Acetadote should be used with caution in patients with asthma, or where there is a history of bronchospasm.

Volume Adjustment: Patients <40kg and Requiring Fluid Restriction
The total volume 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.

For specific treatment information regarding the clinical management of 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.

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category B

There are no adequate and well-controlled studies of Acetadote in pregnant women. However, limited case reports of pregnant women exposed to acetylcysteine during various trimesters did not report any adverse maternal, fetal or neonatal outcomes.

There are published reports on four pregnant women with acetaminophen toxicity, who were treated with oral or intravenous acetylcysteine at the time of delivery. Acetylcysteine crossed the placenta and was measurable following delivery in serum and cord blood of three viable infants and in cardiac blood of a fourth infant at autopsy (22 weeks gestational age who died 3 hours after birth). No adverse sequelae developed in the three viable infants. All mothers recovered and none of the infants had evidence of acetaminophen poisoning.

Reproductive and developmental toxicity studies performed in rats at oral doses up to 6.7 times the recommended human intravenous dose and in rabbits at doses up to 3.3 times the recommended human intravenous dose revealed no evidence of impaired fertility or embryofetal toxicity [see package insert for Reproductive and Developmental Toxicology (13.3)].

Nursing mothers
It is not known whether Acetadote is present in human milk. Because many drugs are excreted in human milk, caution should be exercised when acetylcysteine is administered to a nursing woman. Based on the pharmacokinetics of acetylcysteine, it should be nearly completely cleared 30 hours after administration. Nursing women may consider resuming nursing 30 hours after administration.

Pediatric use
No adverse effects were noted during I.V. infusion with acetylcysteine at a mean rate of 4.2 mg/kg/h for 24 hours to 10 preterm newborns ranging in gestational age from 25 to 31 weeks and in weight from 500 to 1380 grams in one study or in 6 newborns ranging in gestational age from 26 to 30 weeks and in weight from 520 to 1335 grams infused with acetylcysteine at 0.1 to 1.3 mg/kg/h for 6 days. Elimination of acetylcysteine was slower in these infants than in adults; mean elimination half-life was 11 hours. There are no adequate and well-controlled studies in pediatric patients.

Geriatric use
The clinical studies do not provide a sufficient number of geriatric subjects to determine whether the elderly respond differently.

OVERDOSAGE
Single intravenous doses of acetylcysteine at 1000 mg/kg in mice, 2445 mg/kg in rats, 1500 mg/kg in guinea pigs, 1200 mg/kg in rabbits and 500 mg/kg in dogs were lethal. Symptoms of acute toxicity were ataxia, hypoactivity, labored respiration, cyanosis, loss of righting reflex and convulsions.

HOW SUPPLIED/STORAGE AND HANDLING
Acetadote (acetylcysteine) Injection is available as a 20% solution (200mg/mL) in 30 mL single dose glass vials. Acetadote is sterile and can be used for I.V. administration. It is available as follows:

30 mL vials, carton of 4 (NDC 66220-107-30)
Do not use previously opened vials for I.V. administration.

Note: The color of Acetadote may turn from essentially colorless to a slight pink or purple once the stopper is punctured. The color change does not affect the quality of the product.

The stopper in the Acetadote vial is formulated with a synthetic base-polymer and does not contain Natural Rubber Latex, Dry Natural Rubber, or blends of Natural Rubber.

Storage
Store unopened vials at controlled room temperature, 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

Manufactured for:
Cumberland Pharmaceuticals Inc.
Nashville, TN 37203

*Sections or subsections omitted from the Full Prescribing Information are not listed.

PRINCIPAL DISPLAY PANEL - Label

30 mL
Sterile
NDC 66220-107-30
Acetadote®  (acetylcysteine) Injection

200mg/mL (6g/30mL)

CUMBERLAND® PHARMACEUTICALS

Source: Package insert