Acetylcysteine: Package Insert and Label Information (Page 3 of 3)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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 [see Clinical Considerations ]. 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.

Clinical Considerations

Disease-Associated 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.

Data

Animal Data

Reproduction studies have been performed following administration of acetylcysteine during the period of organogenesis in rats at oral doses up to 2,000 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 1,000 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.

8.2 Lactation

Risk Summary

There are no data on the presence of acetylcysteine in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for acetylcysteine and any potential adverse effects on the breastfed child from acetylcysteine or from the underlying maternal condition.

Clinical Considerations

Based on the pharmacokinetic data, acetylcysteine should be nearly completely cleared 30 hours after administration. Breastfeeding women may consider pumping and discarding their milk for 30 hours after administration.

8.4 Pediatric Use

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 [see Dosage and Administration (2.4) ].

10 OVERDOSAGE

Single intravenous doses of acetylcysteine at 1,000 mg/kg in mice, 2,445 mg/kg in rats, 1,500 mg/kg in guinea pigs, 1,200 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.

11 DESCRIPTION

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 C5 H9 NO3 S, and its molecular weight is 163.2. Acetylcysteine has the following structural formula:

Structural Formula

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: 0.5 mg/mL disodium edetate, sodium hydroxide (used for pH adjustment), and Sterile Water for Injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.3 Pharmacokinetics

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.

Distribution

The steady-state volume of distribution (Vdss ) following administration of an intravenous dose of acetylcysteine was 0.47 liter/kg. The protein binding of acetylcysteine ranges from 66% to 87%.

Elimination

Metabolism

Acetylcysteine (i.e., N -acetylcysteine) is postulated to form cysteine and disulfides (N,N-diacetylcysteine and N -acetylcysteine). Cysteine is further metabolized to form glutathione and other metabolites.

Excretion

After a single oral dose of [35 S]-acetylcysteine 100 mg, between 13% to 38% of the total radioactivity administered was recovered in urine within 24 hours. In a separate study, renal clearance was estimated to be approximately 30% of total body clearance.

Specific Populations:

Hepatic Impairment

Following a 600 mg intravenous dose of acetylcysteine to subjects with mild (Child Pugh Class A, n=1), moderate (Child-Pugh Class B, n=4) or severe (Child-Pugh Class C; n=4) hepatic impairment and 6 healthy matched controls, mean T1/2 increased by 80%. Also, the mean CL decreased by 30% and the systemic acetylcysteine exposure (mean AUC) increased 1.6-fold in subjects with hepatic impairment compared to subjects with normal hepatic function. These changes are not considered to be clinically meaningful.

Renal Impairment

Hemodialysis may remove some of total acetylcysteine.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14 CLINICAL STUDIES

Loading Dose/Infusion Rate Study

A randomized, open-label, multi-center clinical study was conducted in Australia in patients with acetaminophen poisoning to compare the rates of hypersensitivity 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 30 years (±13.0).

A subgroup of 58 subjects (33 in the 15-minute infusion group; 25 in the 60-minute infusion 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 infusion group and from 0% to 12% for the 60-minute infusion group.

Observational Study

An open-label, observational database contained information on 1,749 patients who sought treatment for acetaminophen overdose over a 16-year period. Of the 1,749 patients, 65% were female, 34% were male and less than 1% was transgender. Ages ranged from 2 months to 96 years, with 72% of the patients falling in the 16- to 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 to 21 hours) within 8 hours, two (4%) developed hepatotoxicity (AST or ALT greater than 1,000 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. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

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/30 mL (200 mg/mL) of acetylcysteine. Acetylcysteine Injection is sterile and can be used for intravenous administration. It is available as follows:

NDC 17478-660-30 30 mL vials, carton of 4

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.

Storage

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions

Advise patients and caregivers that hypersensitivity reactions related to administration and infusion may occur during and after acetylcysteine treatment, including hypotension, wheezing, shortness of breath and bronchospasm [see Warnings and Precautions (5.1) ].

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.

AKORN
Manufactured by: Akorn, Inc.
Lake Forest, IL 60045

AY00N Rev. 02/17

Principal Display Panel Text for Container Label:

NDC 17478-660-30

Acetylcysteine

Injection

6 g/30 mL

(200 mg/mL)

Must be Further Diluted Prior to

Intravenous Use

30 mL Single dose Vial

Principal Display Panel Text for Container Label
(click image for full-size original)

Principal Display Panel Text for Carton Label:

NDC 17478-660-30

Acetylcysteine

Injection

6 g/30 mL

(200 mg/mL)

Must be Further Diluted Prior to

Intravenous Use

Preservative Free

4 x 30 mL Single dose Vial

Sterile

Rx only Akorn Logo

Principal Display Panel Text for Carton Label
(click image for full-size original)
ACETYLCYSTEINE
acetylcysteine injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:17478-660
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Acetylcysteine (Acetylcysteine) Acetylcysteine 200 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
Edetate Disodium 0.5 mg in 1 mL
Sodium Hydroxide
Water
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:17478-660-30 4 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE
1 30 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (17478-660-30)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA203173 03/25/2015
Labeler — Akorn, Inc. (117696770)
Registrant — Akorn Operating Company LLC (117693100)
Establishment
Name Address ID/FEI Operations
Akorn, Inc. 117696790 PACK (17478-660), LABEL (17478-660)
Establishment
Name Address ID/FEI Operations
Akorn, Inc. 117696832 MANUFACTURE (17478-660), ANALYSIS (17478-660), STERILIZE (17478-660)

Revised: 10/2020 Akorn, Inc.

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