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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Fatal or life-threatening anaphylaxis, rash, hypotension, wheezing, shortness of breath and/or bronchospasm have been observed. Observe patients during and after the infusion; immediately discontinue infusion if a serious reaction occurs and initiate appropriate treatment. Acetylcysteine injection infusion may be carefully restarted after treatment of hypersensitivity has been initiated and acute symptoms have resolved (5.1). Fluid Overload: Total volume administered should be reduced for patients weighing less than 40 kg and for those requiring fluid restriction (5.2). 5.1 Hypersensitivity Reactions Serious acute hypersensitivity reactions;including fatal or life-threatening anaphylaxis,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)] . If a severe hypersensitivity reaction occurs, immediately stop the infusion of Acetylcysteine injection and initiate appropriate treatment. 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 and acute symptoms have resolved; 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. 5.2 Fluid Overload The total volume of Acetylcysteine injection administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. Intravenous administration of Acetylcysteine injection can cause fluid overload, potentially resulting in hyponatremia, seizure and death. To avoid fluid overload, use the recommended dilution [see Dosage and Administration ( 2.5 )].
6 ADVERSE REACTIONS Most common adverse reactions (> 2%) are rash, urticaria/facial flushing and pruritus (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Onesource at 1-888-217-8103 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1)] Fluid Overload [see Warnings and Precautions (5.2)] 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 4. Overall, 17% of patients developed an acute hypersensitivity reaction (18% in the 15-minute infusion group; 14% in the 60-minute infusion group) [see Warnings and Precautions ( 5.1 ), Clinical Studies ( 14 )] . Table 4. Incidence of Drug-Related Adverse Reactions Occurring Within the First 2 Hours Following Study Drug Administration by Preferred Term: Loading Dose/Infusion Rate Study Treatment Group 15-minutes 60-minutes Number of Patients n=109 n=71 Cardiac disorders 5 (5%) 2 (3%) Severity: Tachycardia NOS Unkn Mild Moderate Severe Unkn Mild Moderate Severe 4 (4%) 1 (1%) 2 (3%) Gastrointestinal disorders 16 (15%) 7 (10%) 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%) Severity: Hypersensitivity reaction 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%) Severity: Unkn Mild Moderate Severe Unkn Mild Moderate Severe Pharyngitis Rhinorrhea Rhonchi Throat tightness 1 (1%) 1 (1%) 1 (1%) 1 (1%) Skin & subcutaneous tissue disorders 6 (6%) 5 (7%) 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%) Severity: Flushing Unkn Mild Moderate Severe Unkn Mild Moderate Severe 1 (1%) 1 (1%) 2 (3%) 1 (1%) Unkn= Unknown; NOS= not otherwise specified 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 5 and 6. Table 5. 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% *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 hypersensitivity reactions in pediatric patients receiving intravenous acetylcysteine 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% *Respiratory symptoms are defined as presence of any of the following: cough, wheezing, stridor, shortness of breath, chest tightness, respiratory distress, or bronchospasm. 6.2 Postmarketing Experience Adverse Reactions from Observational Stu dies Observational studies from published literature have described rates of hypersensitivity reactions identified by retrospective chart review in subjects receiving the two-bag regimen after adoption of this regimen as institutional policy in three non-US settings and one US setting compared to a historical control group that received the three-bag regimen. Table 7 displays the incidence of hypersensitivity reactions in patients who received two-bag or three-bag regimens of intravenous acetylcysteine admitted between 2009 to 2020. Table 7. Incidence of Hypersensitivity Reactions in Patients who Received Two-bag or Three-bag Regimens of Intravenous Acetylcysteine in Published Literature Study Hypersensitivity Reactions in Patients Receiving Two-Bag Regimen Hypersensitivity Reactions in Patients Receiving Three-Bag Regimen Study 1 (Three Danish hospitals) 4% (19/507) 16% (47/292) Study 2 (Four Australian hospitals) 5% (8/163) 14% (45/313) Study 3 (Nine Australian hospitals) 1% (17/1300) 7% (65/911) Study 4 (One US hospital) 19% (18/93) 23% (34/150) Adverse Reactions from Postmarketing Spontaneous Reports The following adverse reactions have been identified during post-approval use of Acetylcysteine injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: fatal anaphylaxis