Acetadote

Name: Acetadote

Precautions While Using Acetadote

Your doctor will check your progress closely while you are receiving this medicine. This will allow your doctor to see if the medicine is working properly and to decide if you should continue to receive it. Blood tests may be needed to check for unwanted effects.

This medicine may cause serious allergic reactions, including anaphylaxis. Anaphylaxis requires immediate medical attention. The most serious signs of this reaction are very fast or irregular breathing, gasping for breath, trouble breathing, lightheadedness, dizziness, or fainting. Other signs may include feeling of warmth, redness of the face, neck, arms and occasionally, upper chest, very fast but irregular heartbeat or pulse, hive-like swellings on the skin, and puffiness or swellings of the eyelids or around the eyes. If these side effects occur, get emergency help at once.

Acetadote Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common
  • Fast heartbeat
  • feeling of warmth
  • fever
  • hives or welts, itching, or skin rash
  • hoarseness
  • irritation
  • joint pain, stiffness, or swelling
  • redness of the face, neck, arms, and occasionally, upper chest
  • redness of the skin
  • swelling of the eyelids, face, lips, hands, or feet
  • tightness in the chest
  • trouble breathing or swallowing
Less common
  • Cough
  • fast, pounding, or irregular heartbeat or pulse
  • noisy breathing
Rare
  • Confusion
  • dizziness
  • dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
  • sweating
  • unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Nausea
  • vomiting
Less common
  • Body aches or pain
  • congestion
  • dryness or soreness of the throat
  • fever
  • hoarseness
  • runny nose
  • tender, swollen glands in the neck
  • voice changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Uses of Acetadote

  • It is used to treat acetaminophen overdose.
  • It may be given to you for other reasons. Talk with the doctor.

What are some things I need to know or do while I take Acetadote?

  • Tell all of your health care providers that you take Acetadote. This includes your doctors, nurses, pharmacists, and dentists.
  • The drug may change color when the bottle is opened.
  • There may be a bad odor to this medicine. This most often goes away fast.
  • Very bad and sometimes deadly allergic reactions have rarely happened. Talk with your doctor.
  • If you weigh less than 88 pounds (40 kilograms) or you have to watch how much fluid you take in, talk with your doctor. The chance of too much fluid in the body may be raised with Acetadote. Too much fluid in the body could lead to low blood sodium levels, seizures, and death.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
  • Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Acetadote Dosage and Administration

Pre-Treatment Assessment and Testing Following Acute Acetaminophen Ingestion

The following recommendations are related to acute acetaminophen ingestion. For recommendations related to repeated supratherapeutic exposure see Dosage and Administration (2.5).

  1. Assess the history and timing of acetaminophen ingestion as an overdose.
    • The reported history of the quantity of acetaminophen ingested as an overdose is often inaccurate and is not a reliable guide to therapy.
  2. Obtain the following laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, international normalized ratio (INR), creatinine, blood urea nitrogen (BUN), blood glucose, and electrolytes.
  3. Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion. Acetaminophen concentrations obtained earlier than 4 hours post-ingestion may be misleading as they may not represent maximum acetaminophen concentrations.
  4. If the time of acute acetaminophen ingestion is unknown:
    • Administer a loading dose of Acetadote immediately [see Dosage and Administration (2.4)].
    • Obtain an acetaminophen concentration to determine need for continued treatment [see Dosage and Administration (2.2)].
  5. If the acetaminophen concentration cannot be obtained (or is unavailable or uninterpretable) within the 8-hour time interval after acetaminophen ingestion or there is clinical evidence of acetaminophen toxicity:
    • Administer a loading dose of Acetadote immediately and continue treatment for a total of three doses over 21 hours [see Dosage and Administration (2.4)].
  6. If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known:
    • Administer a loading dose of Acetadote immediately [see Dosage and Administration (2.4)]
    • Obtain an acetaminophen concentration to determine need for continued treatment [see Dosage and Administration (2.2)].
  7. If the patient presents less than 8 hours after ingestion and the time of acute acetaminophen ingestion is known and the acetaminophen concentration is known:
    • Use the Rumack-Matthew nomogram (Figure 1) to determine whether or not to initiate treatment with Acetadote [see Dosage and Administration (2.2)].

Nomogram for Estimating Potential for Hepatoxicity from Acute Acetaminophen Ingestion and Need for Acetadote Treatment

Acetadote is an antidote for acetaminophen overdose. 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.

If the timing of the acute acetaminophen ingestion is known and the results of the acetaminophen assay are available within 8 hours:

  • Refer to the Rumack-Matthew nomogram (see Figure 1) to determine whether or not to initiate treatment with Acetadote.
  • Initiation of Acetadote depends on the plasma or serum acetaminophen concentration and also the clinical presentation of the patient.

The nomogram may underestimate the hepatotoxicity risk in patients with chronic alcoholism, malnutrition, or CYP2E1 enzyme inducing drugs (e.g., isoniazid), and consideration should be given to treating these patients even if the acetaminophen concentrations are in the nontoxic range.

Loading dose

For patients whose acetaminophen concentrations are at or above the “possible” toxicity line (dotted line in nomogram):

  • Administer a loading dose of Acetadote [see Dosage and Administration (2.4)]

For patients with an acute overdose from an extended-release acetaminophen, if the acetaminophen concentration at 4 hours post ingestion is below the possible toxicity line then obtain a second sample for acetaminophen concentration 8 to 10 hours after the acute ingestion. If the second value is at or above the “possible” toxicity line (dotted line in nomogram):

  • Administer a loading dose of Acetadote [see Dosage and Administration (2.4)]

For patients whose values are below the “possible” toxicity line, but time of ingestion was unknown or sample was obtained less than 4 hours after ingestion:

  • Administer a loading dose of Acetadote [see Dosage and Administration (2.4)]

For patients whose values are below the “possible” toxicity line and time of ingestion is known and the sample was obtained more than 4 hours after ingestion, do not administer Acetadote because there is minimal risk of hepatotoxicity.

Figure 1. Rumack-Matthew Nomogram for Estimating Potential for Hepatoxicity for Acetaminophen Posioning – Plasma or Serum Acetaminophen Concentration versus Time (hours) Post-acetaminophen Ingestion

(Adapted from Rumack and Matthew, Pediatrics 1975; 55: 871-876)

Maintenance Dose

Determine need for continued treatment with Acetadote after the loading dose. Choose ONE of the following based on the acetaminophen concentration:

The acetaminophen concentration is above the possible toxicity line according to the nomogram (see Figure 1):

  • Continue Acetadote treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours [see Dosage and Administration (2.4)].
  • Monitor hepatic and renal function and electrolytes throughout treatment.

The acetaminophen concentration could not be obtained:

  • Continue Acetadote treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours [see Dosage and Administration (2.4)].
  • Monitor hepatic and renal function and electrolytes throughout treatment.

For patients whose acetaminophen concentration is below the “possible” toxicity line (see Figure 1) and time of ingestion is known and the sample was obtained more than 4 hours after ingestion:

Discontinue Acetadote.

The acetaminophen concentration was in the non-toxic range, but time of ingestion was unknown or less than 4 hours:

  • Obtain a second sample for acetaminophen concentration and consider the patient's clinical status to decide whether or not to continue Acetadote treatment.
  • If there is any uncertainty as to patient's risk of developing hepatotoxicity, it is recommended to administer a complete treatment course.

Continued Therapy After Completion of Loading and Maintenance Doses

In cases of suspected massive overdose, or with concomitant ingestion of other substances, or in patients with preexisting liver disease; the absorption and/or the half-life of acetaminophen may be prolonged. In such cases, consideration should be given to the need for continued treatment with Acetadote beyond a total of three separate doses over a 21-hour infusion period.

Acetaminophen levels and ALT/AST and INR should be checked after the last maintenance dose. If acetaminophen levels are still detectable, or if the ALT/AST are still increasing or the INR remains elevated; dosing should be continued and the treating physician should contact a US regional poison center at 1-800-222-1222, alternatively, a “special health professional assistance line for acetaminophen overdose” at 1-800-525-6115 for assistance with dosing recommendations, or 1-877-484-2700 for additional information.

Preparation and Storage of Acetadote Diluted Solution Prior to Administration

Because Acetadote is hyperosmolar (2600 mOsmol/L), Acetadote must be diluted in sterile water for injection, 0.45% sodium chloride injection (1/2 normal saline), or 5% dextrose in water prior to intravenous administration [see Warnings and Precautions (5.2)]. Dilution in these three solutions results in different osmolarity of the solution for intravenous administration (see Table 1 for examples of different osmolarity of the solution depending on the type of solution and the Acetadote concentration).

Visually inspect for particular matter and discoloration prior to administration. The color of the diluted solution ranges from colorless to a slight pink or purple once the stopper is punctured (the color change does not affect the quality of the product). The diluted solution can be stored for 24 hours at room temperature. Discard unused portion. If a vial was previously opened, do not use for intravenous administration.

Table 1. Examples of Acetadote Concentration and Osmolarity in Three Solutions

* Adjust osmolarity to a physiologically safe level (generally not less than 150 mOsmol/L in pediatric patients).

Acetadote Concentration Osmolarity
Sterile Water for Injection ½ Normal Saline D5W
7 mg/mL 91 mOsmol/L* 245 mOsmol/L 343 mOsmol/L
24 mg/mL 312 mOsmol/L 466 mOsmol/L 564 mOsmol/L

Recommended Dosage in Adults and Pediatrics for Acute Acetaminophen Ingestion

Acetadote is for intravenous administration only.

Dosage Regimen

The total recommended dosage of Acetadote is 300 mg/kg given intravenously as 3 separate, sequential doses (i.e., 3-bag method to administer the loading, second, and third doses). The total recommended infusion time for 3 doses is 21 hours. For the recommended weight-based dosage and weight-based dilution in patients who weigh:

  • 5 to 20 kg (see Table 2)
  • 21 to 40 kg (see Table 3)
  • 41 kg or greater (see Table 4)
Table 2. Recommended Acetadote Dosage and Dilution for Patients 5 kg to 20 kg

* Dilute Acetadote in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.

** Recommended dosing for those less than 5 kg has not been studied.

Body
Weight
Bag 1 (Loading Dose)
150 mg/kg in 3 mL/kg of diluent* infused over 1 hour
Bag 2 (Second Dose)
50 mg/kg in 7 mL/kg of diluent* infused over 4 hours
Bag 3 (Third Dose)
100 mg/kg diluted in 14 mL/kg of diluent* infused over 16 hours
Loading Dose Diluent
Volume
Second Dose Diluent
Volume
Third Dose Diluent
Volume
5 kg** 750 mg 15 mL 250 mg 35 mL 500 mg 70 mL
10 kg 1,500 mg 30 mL 500 mg 70 mL 1,000 mg 140mL
15 kg 2,250 mg 45 mL 750 mg 105mL 1,500 mg 210mL
20 kg 3,000 mg 60 mL 1,000mg 140mL 2,000 mg 280mL
Table 3. Recommended Acetadote Dosage and Dilution for Patients 21 kg to 40 kg

* Dilute Acetadote in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.

Body
Weight
Bag 1 (Loading Dose)
150 mg/kg in 100 mL of diluent* infused over 1 hour
Bag 2 (Second Dose)
50 mg/kg in 250 mL of diluent* infused over 4 hours
Bag 3 (Third Dose)
100 mg/kg in 500 mL of diluent* infused over 16 hours
21 kg 3,150 mg 1,050 mg 2,100 mg
30 kg 4,500 mg 1,500 mg 3,000 mg
40 kg 6,000 mg 2,000 mg 4,000 mg
Table 4. Recommended Acetadote Dosage and Dilution for Patients 41 kg or Greater

* Dilute Acetadote in one of the following three solutions: sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water.

** No specific studies have been conducted to evaluate the necessity of dose adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg.

Body
Weight
Bag 1 (Loading Dose)
150 mg/kg in 200 mL of diluent* infused over 1 hour
Bag 2 (Second Dose)
50 mg/kg in 500 mL of diluent* infused over 4 hours
Bag 3 (Third Dose)
100 mg/kg in 1000 mL of diluent* infused over 16 hours
41 kg 6,150 mg 2,050 mg 4,100 mg
50 kg 7,500 mg 2,500 mg 5,000 mg
60 kg 9,000 mg 3,000 mg 6,000 mg
70 kg 10,500 mg 3,500 mg 7,000 mg
80 kg 12,000 mg 4,000 mg 8,000 mg
90 kg 13,500 mg 4,500 mg 9,000 mg
≥ 100 kg** 15,000 mg 5,000 mg 10,000 mg

Recommendations for Repeated Supratherapeutic Acetaminophen Ingestion

Repeated supratherapeutic acetaminophen ingestion (RSI) is an ingestion of acetaminophen at dosages higher than those recommended for extended periods of time. The risk of hepatotoxicity and the recommendations for treatment of acute acetaminophen ingestion (i.e., the Rumack-Matthew nomogram) do not apply to patients with RSI. Therefore, obtain the following information to guide Acetadote treatment for RSI:

  • Acetaminophen serum or plasma concentrations. A reported history of the quantity of acetaminophen ingested is often inaccurate and is not a reliable guide to therapy.
  • Laboratory tests to monitor hepatic and renal function and electrolyte and fluid balance: AST, ALT, bilirubin, INR, creatinine, BUN, blood glucose, and electrolytes.

For specific Acetadote dosage and administration information in patients with RSI, consider contacting 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.

Contraindications

Acetadote is contraindicated in patients with a previous hypersensitivity reaction to acetylcysteine [see Warnings and Precautions (5.1)].

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 in the animals 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 (200 mg/mL) in 30 mL single-dose glass vials. Each single dose vial contains 6 g/30mL (200 mg/mL) of Acetadote injection. Acetadote is sterile and can be used for intravenous administration. It is available as follows:

  • 30 mL vials, carton of 4 (NDC 66220-207-30)

Do not use previously opened vials for intravenous 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.

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

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 glucuronide 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 Intravenous 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.

Pharmacokinetics

Distribution

The steady-state volume of distribution (Vdss) and the protein binding for acetylcysteine were reported to be 0.47 liter/kg and 83%, respectively.

Metabolism

Acetylcysteine may form cysteine, disulfides and conjugates in vivo (N, N'-diacetylcysteine, N-acetylcysteine-cysteine, N-acetylcysteine-glutathione, N-acetylcysteine-protein, etc). Based on published data, it was reported that after an oral dose of 35S-acetylcysteine, about 22% of total radioactivity was excreted in urine after 24 hours. No metabolites were identified.

Elimination

After a single intravenous dose of acetylcysteine, the plasma concentration of total acetylcysteine declined in a poly-exponential decay manner with a mean terminal half-life (T½) of 5.6 hours. The mean clearance (CL) for acetylcysteine was reported to be 0.11 liter/hr/kg and renal CL constituted about 30% of total CL.

Special Populations

Gender: Adequate information is not available to assess if there are differences in pharmacokinetics (PK) between males and females.

Pediatric: The mean elimination T½ of acetylcysteine is longer in newborns (11 hours) than in adults (5.6 hours). Pharmacokinetic information is not available in other age groups.

Pregnant Women: In four pregnant women with acetaminophen toxicity, oral or intravenous acetylcysteine was administered at the time of delivery. Acetylcysteine was detected in the cord blood of 3 viable infants and in cardiac blood of a fourth infant sampled at autopsy [see Pregnancy].

Hepatic Impairment: In subjects with severe liver damage, i.e., cirrhosis due to alcohol (with Child-Pugh score of 7-13), or primary and/or secondary biliary cirrhosis (with Child-Pugh score of 5-7), mean T½ increased by 80% while mean CL decreased by 30% compared to the control group.

Renal Impairment: Pharmacokinetic information is not available in patients with renal impairment.

Geriatric Patients: Adequate information on acetylcysteine PK in geriatric patients is not available.

Clinical Studies

Loading Dose/Infusion Rate Study

A randomized, open-label, multi-center clinical study was conducted in Australia to compare the rates of anaphylactoid reactions between two rates of infusion for the intravenous acetylcysteine loading dose. One hundred nine subjects were randomized to a 15 minute infusion rate and seventy-one subjects were randomized to a 60 minute infusion rate. The loading dose was 150 mg/kg followed by a maintenance dose of 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours. Of the 180 patients, 27% were male and 73% were female. Ages ranged from 15 to 83 years, with the mean age being 29.9 years (+13.0).

A subgroup of 58 subjects (33 in the 15-minute treatment group; 25 in the 60-minute treatment group) was treated within 8 hours of acetaminophen ingestion. No hepatotoxicity occurred within this subgroup; however with 95% confidence, the true hepatotoxicity rates could range from 0% to 9% for the 15-minute treatment group and from 0% to 12% for the 60-minute treatment group.

Observational Study

An open-label, observational database contained information on 1749 patients who sought treatment for acetaminophen overdose over a 16-year period. Of the 1749 patients, 65% were female, 34% were male and less than 1% was transgender. Ages ranged from 2 months to 96 years, with 71.4% of the patients falling in the 16-40 year old age bracket. A total of 399 patients received acetylcysteine treatment. A post-hoc analysis identified 56 patients who (1) were at high or probable risk for hepatotoxicity (APAP greater than 150 mg/L at the four hours line according to the Australian nomogram) and (2) had a liver function test. Of the 53 patients who were treated with intravenous acetylcysteine (300 mg/kg intravenous acetylcysteine administered over 20-21 hours) within 8 hours, two (4%) developed hepatotoxicity (AST or ALT greater than 1000 U/L). Twenty-one of 48 (44%) patients treated with acetylcysteine after 15 hours developed hepatotoxicity. The actual number of hepatotoxicity outcomes may be higher than what is reported here. For patients with multiple admissions for acetaminophen overdose, only the first overdose treated with intravenous acetylcysteine was examined. Hepatotoxicity may have occurred in subsequent admissions.

Evaluable data were available from a total of 148 pediatric patients (less than 16 years of age) who were admitted for poisoning following ingestion of acetaminophen, of whom 23 were treated with intravenous acetylcysteine. Of the 23 patients who received intravenous acetylcysteine treatment, 3 patients (13%) had an adverse reaction (anaphylactoid reaction, rash and flushing, transient erythema). There were no deaths of pediatric patients. None of the pediatric patients receiving intravenous acetylcysteine developed hepatotoxicity while two patients not receiving intravenous acetylcysteine developed hepatotoxicity. The number of pediatric patients is too small to provide a statistically significant finding of efficacy; however the results appear to be consistent to those observed for adults.

Postmarketing Safety Study [see Clinical Studies Experience]

FDA approves Acetadote

The U.S. Food and Drug Administration (FDA) has approved Acetadote, an injectable drug used to treat acetaminophen overdose.

Acetadote (acetylcysteine) injection will be used in an emergency room setting to prevent or lessen potential liver damage resulting from an overdose of acetaminophen, the leading cause of drug toxicity in the United States. According to the FDA, more than 56,000 emergency room visits and 100 deaths occur each year due to unintentional overdoses of acetaminophen, a common ingredient in many over-the-counter painkillers. 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.

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