ACETYLCYSTEINE- acetylcysteine injection, solution
APP Pharmaceuticals, LLC
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ACETYLCYSTEINE INJECTION safely and effectively. See full prescribing information for ACETYLCYSTEINE INJECTION.
ACETYLCYSTEINE INJECTION Initial U.S. Approval: 2004. RECENT MAJOR CHANGESAdverse Reactions, Postmarketing Safety Study (6.1) 12/2008 INDICATIONS AND USAGEAcetylcysteine Injection, administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or lessen hepatic injury (1) DOSAGE AND ADMINISTRATIONPatients ≥40 kg (2.1): Loading Dose: 150 mg/kg in 200 mL of diluent administered over 60 min Dose 2: 50 mg/kg in 500 mL of diluent administered over 4 hr Dose 3: 100 mg/kg in 1000 mL of diluent administered over 16 hr Patients >20- <40 kg (2.1): 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 (2.1): 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 DOSAGE FORMS AND STRENGTHSVials: 200 mg/mL, 30 mL (20% solution) (3) CONTRAINDICATIONSPatients with previous anaphylactoid reaction to acetylcysteine (4) WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSMost common adverse reactions (incidence >2%) are rash, urticaria/facial flushing and pruritus (6.1) To report SUSPECTED ADVERSE REACTIONS, contact APP Pharmaceuticals, LLC, Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONSNo drug-drug interaction studies have been conducted (7) USE IN SPECIFIC POPULATIONSSee 17 for PATIENT COUNSELING INFORMATION. Revised: 5/2011 |
Acetylcysteine Injection, 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.
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 – 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.
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 total dose of Acetylcysteine Injection is 300 mg/kg administered over 21 hours.Please refer to the guidelines below for dose preparation based upon patient weight.
Table 1. Three-Bag Method Dosage Guide by Weight, patients ≥ 40 kg
Body Weight
| LOADING Dose 150 mg/kg in 200 mL diluent * over 60 min | SECOND Dose 50 mg/kg in 500 mL diluent over 4 hours | THIRD Dose 100 mg/kg in 1000 mL diluent over 16 hours |
|
(kg)
| (lb)
| Acetylcysteine Injection (mL)
| Acetylcysteine Injection (mL)
| Acetylcysteine Injection (mL)
|
100 | 220 | 75 | 25 | 50 |
90 | 198 | 67.5 | 22.5 | 45 |
80 | 176 | 60 | 20 | 40 |
70 | 154 | 52.5 | 17.5 | 35 |
60 | 132 | 45 | 15 | 30 |
50 | 110 | 37.5 | 12.5 | 25 |
40 | 88 | 30 | 10 | 20 |
*Acetylcysteine Injection is hyperosmolar (2600 mOsm/L) and is compatible with 5% Dextrose (D5W), ½Normal Saline (0.45% Sodium Chloride Injection, ½ NS), and Water for Injection (WFI).
Table 2. Three-Bag Method Dosage Guide by Weight, patients >20 - < 40 kg
Body Weight | LOADING Dose 150 mg/kg over 60 minutes | SECOND Dose 50 mg/kg over 4 hours | THIRD Dose 100 mg/kg over 16 hours |
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(kg)
| (lb)
| Acetylcysteine Injection(mL)
| Diluent* (mL)
| Acetylcysteine Injection (mL)
| Diluent(mL)
| Acetylcysteine Injection(mL)
| Diluent(mL)
|
30 | 66 | 22.5 | 100 | 7.5 | 250 | 15 | 500 |
25 | 55 | 18.75 | 100 | 6.25 | 250 | 12.5 | 500 |
Patients ≤20 kg (Table 3):
Loading Dose: 150 mg/kg in 3 mL/kg of body weight of diluent* administered over 60 min
Second Dose: 50 mg/kg in 7 mL/kg of body weight of diluent administered over 4 hr
Third Dose: 100 mg/kg in 14 mL/kg of body weight of diluent administered over 16 hr
Table 3. Three-Bag Method Dosage Guide by Weight, patients ≤ 20 kg
Body Weight
| LOADING Dose 150 mg/kg over 60 minutes | SECOND Dose 50 mg/kg over 4 hours | THIRD Dose 100 mg/kg over 16 hours |
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(kg)
| (lb)
| Acetylcysteine Injection (mL)
| Diluent*(mL)
| Acetylcysteine Injection(mL)
| Diluent (mL)
| Acetylcysteine Injection(mL)
| Diluent (mL)
|
20 | 44 | 15 | 60 | 5 | 140 | 10 | 280 |
15 | 33 | 11.25 | 45 | 3.75 | 105 | 7.5 | 210 |
10 | 22 | 7.5 | 30 | 2.5 | 70 | 5 | 140 |
*Acetylcysteine Injection is hyperosmolar (2600 mOsm/L) and is compatible with 5% Dextrose (D5W), ½Normal Saline (0.45% Sodium Chloride Injection, ½ NS), and Water for Injection (WFI).
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 Acetylcysteine Injection may turn from essentially colorless to a slight pink color once the stopper is punctured. The color change does not affect the quality of the product.
No data are available to determine if a dose adjustment in patients with moderate or severe renal impairment is required.
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.
Acetylcysteine Injection is contraindicated in patients with previous anaphylactoid reactions to acetylcysteine.
Serious anaphylactoid reactions, including death in a patient with asthma, have been reported in patients administered acetylcysteine intravenously.
Acetylcysteine Injection should be used with caution in patients with asthma, or where there is a history of bronchospasm.
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 I.V. acetylcysteine administration were rash, urticaria and pruritus. The frequency of adverse reactions has been reported to be between 0.2% and 20.8%, and they most commonly occur during the initial loading dose of acetylcysteine.
Loading Dose/Infusion Rate Study
The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration reported in a randomized study in patients with acetaminophen poisoning is presented in Table 4 by preferred term. In this study patients were randomized to a 15-minute or a 60-minute loading dose regimen.
Within the first 2 hours following I.V. acetylcysteine administration, 17% developed an anaphylactoid reaction (18% in the 15-minute treatment group; 14% in the 60-minute treatment group) in this randomized, open-label, multi-center clinical study conducted in Australia to compare the rates of anaphylactoid reactions between two rates of infusion for the I.V. acetylcysteine loading dose [ see WARNINGS (Section 5) and CLINACAL STUDIES - Loading Dose/InfusionRate Study(Section 14)].
Treatment
Group | 15-min
| 60-min
|
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Number of Patients
| n=109
| n=71
|
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Cardiac disorders | 5 (5%) | 2 (3%) |
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Severity:
Tachycardia NOS | Unkn
| Mild
| Moderate
| Severe
| Unkn
| Mild
| Moderate
| Severe
|
| 4 (4%) | 1 (1%) | | | 2 (3%) | | |
|
Gastrointestinal disorders | 16 (15%) | 7 (10%) |
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Severity:
Nausea Vomiting NOS | Unkn
| Mild
| Moderate
| Severe
| Unkn
| Mild
| Moderate
| Severe
|
1(1%) | | 6 (6%) | | | 1 (1%) | 1 (1%) | |
|
| 2 (2%) | 11 (10%) | | | 2 (3%) | 4 (6%) | |
|
Immune System Disorders | 20 (18%) | 10 (14%) |
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Severity:
Anaphylactoid reaction | Unkn
| Mild
| Moderate
| Severe
| Unkn
| Mild
| Moderate
| Severe
|
2(2%) | 6 (6%) | 11 (10%) | 1 (1%) | | 4 (6%) | 5 (7%) | 1 (1%) |
|
Respiratory, thoracic and mediastinal disorders | 2 (2%) | 2 (3%) |
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Severity:
Pharyngitis Rhinorrhoea Rhonchi Throat tightness | Unkn
| Mild
| Moderate
| Severe
| Unkn
| Mild
| Moderate
| Severe
|
| | 1 (1%) | | | | | |
|
| 1 (1%) | | | | | | |
|
| | | | | 1 (1%) | | |
|
| | | | | 1 (1%) | | |
|
Skin & subcutaneous tissue disorders | 6 (6%) | 5 (7%) |
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Severity:
Pruritus Rash NOS | Unkn
| Mild
| Moderate
| Severe
| Unkn
| Mild
| Moderate
| Severe
|
| 1 (1%) | | | | 2 (3%) | | |
|
| 3 (3%) | 2 (2%) | | | 3 (4%) | | |
|
Vascular disorders | 2 (2%) | 3 (4%) |
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Severity:
Flushing | Unkn
| Mild
| Moderate
| Severe
| Unkn
| Mild
| Moderate
| Severe
|
| 1 (1%) | 1 (1%) | | | 2 (3%) | 1 (1%) | |
|
Unkn=Unknown
|
| Incidence (%)
|
Reaction
| % of Patients (n=4709)
|
Urticaria/Facial Flushing | 6.1% |
Pruritus | 4.3% |
Respiratory Symptoms* | 1.9% |
Edema | 1.6% |
Hypotension | 0.1% |
Anaphylaxis | 0.1% |
*Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.
Table 6. Distribution of reported reactions in pediatric patients receiving I.V. NAC
| Incidence (%)
|
Reaction
| % of Patients (n=1905) |
Urticaria/Facial Flushing | 7.6% |
Pruritus | 4.1% |
Respiratory Symptoms* | 2.2% |
Edema | 1.2% |
Anaphylaxis | 0.2% |
Hypotension | 0.1% |
*Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.
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 Reproductive and Developmental Toxicology (13.3)].
It is not known whether Acetylcysteine Injection 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.
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.
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.
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.
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:
Special Populations:
Gender:Adequate information is not available to assess if there are differences in pharmacokinetics (PK) between males and females.
Geriatric Patients: Adequate information on acetylcysteine PK in geriatric patients is not available.
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 (0.8 times the recommended human dose of 300 mg/kg) did not affect the fertility or general reproductive performance.
Reproduction studies were performed in rats at oral doses up to 2000 mg/kg/day (6.7 times the recommended human dose of 300 mg/kg) and in rabbits at oral doses up to 1000 mg/kg/day (3.3 times the recommended human dose of 300 mg/kg) and revealed no evidence of impaired fertility or harm to the fetus due to acetylcysteine [see Pregnancy (8.1)].
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 I.V. 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 <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 >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 I.V. acetylcysteine (300 mg/kg I.V. acetylcysteine administered over 20-21 hours) within 8 hours, two (4%) developed hepatotoxicity (AST or ALT>1000U/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 I.V. 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 I.V. acetylcysteine. Of the 23 patients who received I.V. 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 I.V. acetylcysteine developed hepatotoxicity while two patients not receiving I.V. 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 6.1 Clinical Studies Experience]
Do not use previously opened vials for I.V. 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.
Storage
Store unopened vials at controlled room temperature, 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
ACETYLCYSTEINE
acetylcysteine injection, solution |
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Labeler - APP Pharmaceuticals, LLC (608775388) |