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Label Changes for:

Acetadote (acetylcysteine) Injection

July 2016

Changes have been made to the WARNINGS, PRECAUTIONS and ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

July 2016

WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions replaces Anaphylactoid subheading (subsection revised)
  • 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…..( refer to Label)
Fluid Overload replaces Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction Fluid Overload subheading (subsection revised)
  • The total volume of ACETADOTE 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. If volume is not adjusted fluid overload can occur, potentially resulting in hyponatremia, seizure and death.
  • Intravenous administration of ACETADOTE 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.

ADVERSE REACTIONS

Clinical Studies Experience
Table 5. Incidence of Drug-Related Adverse Reactions Occurring Within the First 2 Hours Following Study Drug Administration by Preferred Term: Loading Dose/Infusion Rate Study
  • Anaphylaxis changed to Hypersensitivity
Table 7. Distribution of reported hypersensitivity reactions in pediatric patients receiving intravenous acetylcysteine
  • Anaphylaxis changed to Hypersensitivity

USE IN SPECIFIC POPULATIONS

PLLR Conversion:

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. 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 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.
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 ACETADOTE and any potential adverse effects on the breastfed child from ACETADOTE 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.
Pediatric Use (Section revised)
  • Safety and effectiveness of ACETADOTE in pediatric patients have not been established by adequate and well controlled studies. Use of ACETADOTE in pediatric patients 5 kg and greater is based on clinical practice

PATIENT COUNSELING INFORMATION

Hypersensitivity Reactions (section revised)
  • Advise patients and caregivers that hypersensitivity reactions related to administration and infusion may occur during and after ACETADOTE treatment, including hypotension, wheezing, shortness of breath and bronchospasm.
  • 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.
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