The following Structured Product Label (SPL) was submitted to the FDA by Hikma Pharmaceuticals Usa Inc. for the product Acetylcysteine (NDC 0143-9433). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, 2.1 pre-treatment assessment and testing following acute acetaminophen ingestion, 2.2 nomogram for estimating potential for hepatoxicity from acute acetaminophen ingestion and need for acetylcysteine injection treatment, 2.3 preparation and storage of acetylcysteine injection diluted solution prior to administration, 2.4 recommended dosage in adults and pediatrics for acute acetaminophen ingestion, 2.5 recommendations for repeated supratherapeutic acetaminophen ingestion, 2.6 recommendations for repeated supratherapeutic acetaminophen ingestion, 3 dosage forms and strengths, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
Acetylcysteine injection is indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with acute ingestion or from repeated supratherapeutic ingestion (RSI).
Prior to initiating treatment with Acetylcysteine injection, decide whether the three-bag or two-bag regimen will be used [see Dosage and Administration (2.4)].
The following recommendations are related to acute acetaminophen ingestion.
For recommendations related to repeated supratherapeutic exposure [see Dosage and Administration (2.6)].
Acetylcysteine injection 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:
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.
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 [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 Acetylcysteine injection 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.
| Acetylcysteine injection Concentration | Osmolarity | ||
|---|---|---|---|
| Sterile Water for Injection | ½ Normal Saline | D5W | |
| 7 mg/mL | 91 mOsmol/L Adjust osmolarity to a physiologically safe level (generally not less than 150 mOsmol/L in pediatric patients). | 245 mOsmol/L | 343 mOsmol/L |
| 24 mg/mL | 312 mOsmol/L | 466 mOsmol/L | 564 mOsmol/L |
Acetylcysteine injection is for intravenous administration only.
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 Acetylcysteine injection treatment for RSI:
For specific Acetylcysteine injection 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.
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 revised Rumack-Matthew nomogram) do not apply to patients with RSI.
Therefore, obtain the following information to guide Acetylcysteine injection 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 Acetylcysteine injection 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.
Injection: 200 mg/mL (6 grams of acetylcysteine in 30 mL) in a single-dose vial.
Acetylcysteine injection is contraindicated in patients with a previous hypersensitivity reaction to acetylcysteine [see Warnings and Precautions (5.1)].
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.
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)].
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.
Safety and effectiveness of Acetylcysteine injection in pediatric patients have not been established by adequate and well-controlled studies. Use of Acetylcysteine injection in pediatric patients 5 kg and greater is based on clinical practice [see Dosage and Administration (2.4)].
An initial 150 mg/kg dose of acetylcysteine for a patient weighting 106 kg was mistakenly calculated as 160 g (a decimal point error resulting in a 10-fold higher than prescribed dose). An hour after the infusion started, the patient complained of generalized heat sensation and body pain and developed widespread urticaria and hypotension. The second acetylcysteine infusion was withheld and the patient was treated for anaphylaxis. Despite treatment the patient subcomed to the acute inflammatory reaction and died.
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.
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 C5H9NO3S, and its molecular weight is 163.2. Acetylcysteine has the following structural formula:
Chemical Structure (Acetylcysteine Injection 2)
Acetylcysteine injection is supplied as a sterile solution in vials containing 20% w/v (200 mg/mL) acetylcysteine. The pH of the solution ranges from 6.0 to 7.5. Acetylcysteine injection contains the following inactive ingredients: sodium hydroxide (used for pH adjustment), Disodium Edetate Dihydrate and Sterile Water for Injection, USP.
Acetylcysteine has been shown to reduce the extent of liver injury following acetaminophen overdose. Acetaminophen doses of 150 mg/kg or greater have been associated with hepatotoxicity. Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite of acetaminophen.
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 (T1/2) of 5.6 hours. The mean clearance (CL) for acetylcysteine was 0.11 liter/hr/kg and renal CL constituted about 30% of the total CL.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of acetylcysteine.
Acetylcysteine was not genotoxic in the Ames test or the in vivo mouse micronucleus test. It was, however, positive in the in vitro mouse lymphoma cell (L5178Y/TK+/-) forward mutation test.
Treatment of male rats with acetylcysteine at an oral dose of 250 mg/kg/day for 15 weeks (0.1 times the recommended total human intravenous dose of 300 mg/kg based on body surface comparison) did not affect the fertility or general reproductive performance.
Acetylcysteine injection (acetylcysteine) 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 Acetylcysteine injection. Acetylcysteine injection is sterile and can be used for intravenous administration. It is available as follows:
• Carton of 4 x 30 mL Single-Dose Vials (NDC 0143-9433-04)
• 30 mL Single-Dose Vial (NDC 0143-9433-01)
Do not use previously opened vials 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.
The stopper in the Acetylcysteine injection vial is formulated with a synthetic base-polymer and does not contain Natural Rubber Latex, Dry Natural Rubber, or blends of Natural Rubber.
NDC 0143-9433-01
Rx Only
Acetylcysteine
Injection
6 g/30 mL (200 mg/mL)
MUST BE FURTHER DILUTED
PRIOR TO INTRAVENOUS USE
onesource
Hikma
PHARMACEUTICALS USA Inc.
Vial Label (Acetylcysteine Injection 3)
NDC 0143-9433-04
Rx Only
Acetylcysteine
Injection
6 g/30 mL (200 mg/mL)
MUST BE FURTHER DILUTED
PRIOR TO INTRAVENOUS USE
4 x 30 mL Sterile Single-Dose Vials
onesource
Hikma
PHARMACEUTICALS USA Inc.
Carton Label (Acetylcysteine Injection 4)
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