Acetylcysteine Drug Information

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). Acetylcysteine Injection is an antidote for acetaminophen overdose indicated to prevent or lessen hepatic injury after ingestion of a potentially hepatotoxic quantity of acetaminophen in patients with an acute ingestion or from repeated supratherapeutic ingestion (RSI).

Clinical Studies Experience

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.

Loading Dose/Infusion Rate Study In a randomized, open-label, multi-center clinical study conducted in Australia in patients with acetaminophen poisoning, the rates of hypersensitivity reactions between a 15-minute and 60-minute intravenous infusion for the 150 mg/kg loading dose of acetylcysteine were compared. The incidence of drug-related adverse reactions occurring within the first 2 hours following acetylcysteine administration is presented in Table 5. Overall, 17% of patients developed an acute hypersensitivity reaction (18% in the 15-minute infusion group; 14% in the 60-minute infusion group) . 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 Unkn=Unknown; NOS=not otherwise specified Treatment Group 15-minutes 60-minutes Number of Patients n=109 n=71 Cardiac disorders 5 (5%) 2 (3%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Tachycardia NOS 4 (4%) 1 (1%) 2 (3%) Gastrointestinal disorders 16 (15%) 7 (10%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Nausea 1 (1%) 6 (6%) 1 (1%) 1 (1%) Vomiting NOS 2 (2%) 11 (10%) 2 (3%) 4 (6%) Immune System Disorders 20 (18%) 10 (14%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Hypersensitivity reaction 2 (2%) 6 (6%) 11 (10%) 1 (1%) 4 (6%) 5 (7%) 1 (1%) Respiratory, thoracic and mediastinal disorders 2 (2%) 2 (3%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pharyngitis 1 (1%) Rhinorrhoea 1 (1%) Rhonchi 1 (1%) Throat tightness 1 (1%) Skin & subcutaneous tissue disorders 6 (6%) 5 (7%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pruritus 1 (1%) 2 (3%) Rash NOS 3 (3%) 2 (2%) 3 (4%) Vascular disorders 2 (2%) 3 (4%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Flushing 1 (1%) 1 (1%) 2 (3%) 1 (1%) Safety Study A large multi-center study was performed in Canada where data were collected from patients who were treated with intravenous acetylcysteine for acetaminophen overdose between 1980 and 2005. This study evaluated 4709 adult cases and 1905 pediatric cases. The incidence of hypersensitivity reactions in adult (overall incidence 8%) and pediatric (overall incidence 10%) patients is presented in Tables 6 and 7. Table 6. Distribution of Reported Hypersensitivity Reactions in Adult Patients Receiving Intravenous Acetylcysteine Reaction Incidence (%) n=4709 Urticaria/Facial Flushing 6.1% Pruritus 4.3% Respiratory Symptoms* 1.9% Edema 1.6% Hypotension 0.1% Anaphylaxis 0.1% Table 7. Distribution of Reported Hypersensitivity Reactions in Pediatric Patients Receiving Intravenous Acetylcysteine *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm.

Reaction Incidence (%) n=1905 Urticaria/Facial Flushing 7.6% Pruritus 4.1% Respiratory Symptoms* 2.2% Edema 1.2% Anaphylaxis 0.2% Hypotension 0.1%

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. 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.

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.

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

An initial 150 mg/kg dose of acetylcysteine for a patient weighing 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 succumbed 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.