RHINOFLUIMUCIL

Acetylcysteine is an antioxidant and glutathione inducer indicated for mucolytic therapy and the treatment of acetaminophen overdose. 14, 15, 16, 17 Acetylcysteine has also been studied for a wide variety of off-label indications with mixed results. 8, 9, 10 Acetylcysteine was granted FDA approval on 14 September 1963.

Acetylcysteine is indicated for mucolytic therapy and in the management of acetaminophen overdose. 14, 15, 16,

Acetylcysteine is indicated for mucolytic therapy and in the management of acetaminophen overdose. 14, 15, 16, 17 It has a short duration of action as it is given every 1-8 hours depending on route of administration, and has a wide therapeutic window. 14, 15, 16, 17 Patients should be counselled regarding diluting oral solutions in cola for taste masking, 7 the risk of hypersensitivity, and the risk of upper gastrointestinal hemorrhage. 14, 15, 16, 17.

An 11 g dose in the form of an effervescent tablet for solution reaches a mean C max of 26.5 µg/mL, with a T max of 2 hours, and an AUC of 186 µg*h/mL.

The volume of distribution of acetylcysteine is 0.47 L/kg.

Acetylcysteine can be deacetylated by aminoacylase 1 or other undefined deacetylases before undergoing the normal metabolism of cysteine. 1, 5 Hover over products below to view reaction partners Acetylcysteine Cysteine.

An oral dose of radiolabelled acetylcysteine is 13-38% recovered in the urine in the first 24 hours, 15 while 3% is recovered in the feces.

The mean terminal half life of acetylcysteine in adults is 5.6 hours and in pre-term neonates is 11 hours.

Acetylcysteine has a mean clearance of 0.11 L/hr/kg.

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Patients experiencing an overdose may present with vomiting, nausea, bronchospasm, periorbital angioedema, and hypotension.

Treat patients with symptomatic and supportive measures.

Hemodialysis may remove some acetylcysteine from circulation as it is somewhat protein bound.

Acetylcysteine is contraindicated in patients with a previous hypersensitivity reaction to acetylcysteine.

Patients with a previous hypersensitivity reaction to acetylcysteine.

Obtain a plasma or serum sample to assay for acetaminophen concentration at least 4 hours after ingestion.

If the time of acetaminophen ingestion is unknown: Administer a loading dose of acetylcysteine injection immediately.

Obtain an acetaminophen concentration to determine need for continued treatment.

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 acetylcysteine injection immediately and continue treatment for a total of three doses over 21 hours.

If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known: Administer a loading dose of acetylcysteine injection immediately.

Obtain acetaminophen concentration to determine need for continued treatment.

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 acetylcysteine injection.

Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion: See Full Prescribing Information for instructions on how to use the nomogram to determine the need for dosing.

Preparation and Storage of Diluted Solution Prior to Administration: Acetylcysteine injection is hyperosmolar (2600 mOsmol/L), therefore acetylcysteine injection must be diluted in sterile water for injection, 0.45% sodium chloride injection, or 5% dextrose in water injection prior to intravenous administration.

Information for examples of osmolarity depending on the type of solution and acetylcysteine injection concentration.

Acetylcysteine injection is for intravenous administration only.

Total dosage of acetylcysteine injection is 300 mg/kg given intravenously as 3 separate doses and total recommended infusion time for 3 doses is 21 hours.

Information for weight-based dosage and weight-based dilution.

Information for recommendations for continuing acetylcysteine injection treatment after 21 hours.

Repeated Supratherapeutic Acetaminophen Ingestion

Obtain acetaminophen concentration and other laboratory tests to guide treatment; Rumack-Matthew nomogram does not apply. 2.1 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.

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.

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.

Acetaminophen concentrations obtained earlier than 4 hours post-ingestion may be misleading as they may not represent maximum acetaminophen concentrations.

If the time of acute acetaminophen ingestion is unknown: Administer a loading dose of acetylcysteine injection immediately.

If the patient presents more than 8 hours after ingestion and the time of acute acetaminophen ingestion is known: Administer a loading dose of acetylcysteine injection immediately Obtain an acetaminophen concentration to determine need for continued treatment.

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 acetylcysteine injection. 2.2 Nomogram for Estimating Potential for Hepatotoxicity from Acute Acetaminophen Ingestion and Need for Acetylcysteine Injection Treatment Acetylcysteine injection is an antidote for acetaminophen overdose.

The critical ingestion-treatment interval for maximal protection against severe hepatic injury is between to 8 hours.

Efficacy diminishes progressively after 8 hours and treatment initiation between 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 to determine whether or not to initiate treatment with acetylcysteine injection.

Initiation of acetylcysteine injection 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 acetylcysteine injection.

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 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 acetylcysteine injection.

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 acetylcysteine injection.

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 acetylcysteine injection because there is minimal risk of hepatotoxicity.

Figure 1.

Rumack-Matthew Nomogram for Estimating Potential for Hepatotoxicity for Acetaminophen Poisoning – Plasma or Serum Acetaminophen Concentration versus Time (hours) Post-acetaminophen Ingestion (Adapted from Rumack and Matthew, Pediatrics 1975; 55: 871-876) Figure 1 Maintenance Dose Determine need for continued treatment with acetylcysteine injection 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: Continue acetylcysteine injection treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours.

Monitor hepatic and renal function and electrolytes throughout treatment.

The acetaminophen concentration could not be obtained: Continue acetylcysteine injection treatment with the maintenance dose for a total of three separate doses over an infusion period of 21 hours.

For patients whose acetaminophen concentration is below the “possible” toxicity line and time of ingestion is known and the sample was obtained more than 4 hours after ingestion: Discontinue acetylcysteine injection.

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 acetylcysteine injection 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 acetylcysteine injection 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 1-866-625-1618 for additional information. 2.3 Preparation and Storage of Acetylcysteine Injection Diluted Solution Prior to Administration Because acetylcysteine injection is hyperosmolar (2600 mOsmol/L), acetylcysteine injection 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.

Dilution in these three solutions results in different osmolarity of the solution for intravenous administration.

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 Acetylcysteine Injection Concentration and Osmolarity in Three Solutions * Adjust osmolarity to a physiologically safe level (generally not less than 150 mOsmol/L in pediatric patients).

Acetylcysteine Injection Concentration Osmolarity Sterile Water for Injection ½ Normal Saline D5W 7 mg per mL 91 mOsmol/L* 245 mOsmol/L 343 mOsmol/L 24 mg per mL 312 mOsmol/L 466 mOsmol/L 564 mOsmol/L 2.4 Recommended Dosage in Adults and Pediatrics for Acute Acetaminophen Ingestion Acetylcysteine injection is for intravenous administration only.

The total recommended dosage of acetylcysteine i.

Injection is supplied as a 20% solution (200 mg per mL) as follows: NDC Acetylcysteine Injection (200 mg per mL) Package Factor 25021-812-66 6 grams per 30 mL Single-Dose Vial 4 vials per carton Do not use previously opened vials for intravenous administration.

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.

Store unopened vials at 20° to 25°C (68° to 77°F).

Discard unused portion.

The container closure is not made with natural rubber latex.

Store unopened vials at 20° to 25°C (68° to 77°F).

Discard unused portion.

The container closure is not made with natural rubber latex.

Limited published case reports and case series of pregnant women exposed to acetylcysteine during various trimesters are not sufficient to inform any drug associated risk.

Delaying treatment of acetaminophen overdose may increase the risk of maternal or fetal morbidity and mortality.

Reproduction studies in rats and rabbits following oral administration of acetylcysteine during the period of organogenesis at doses similar to the total intravenous dose (based on the body surface area) did not cause any adverse effects to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Maternal and/or Embryo/Fetal Risk Acetaminophen and acetylcysteine cross the placenta.

Delaying treatment in pregnant women with acetaminophen overdose and potentially toxic acetaminophen plasma levels may increase the risk of maternal and fetal morbidity and mortality.

Reproduction studies have been performed following administration of acetylcysteine during the period of organogenesis in rats at oral doses up to 2000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison) and in rabbits at oral doses up to 1000 mg/kg/day (1.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface area comparison).

No adverse developmental outcomes due to acetylcysteine were observed.

Safety and effectiveness of acetylcysteine in pediatric patients have not been established by adequate and well-controlled studies.

Use of acetylcysteine in pediatric patients 5 kg and greater is based on clinical practice.