NEOSTIGMINE METHYLSULFATE

5 WARNINGS AND PRECAUTIONS 5.1. Bradycardia Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to Neostigmine Methylsulfate Injection, USP, to lessen the risk of bradycardia [see DOSAGE AND ADMINISTRATION (2.4)]. 5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions Neostigmine Methylsulfate Injection, USP, should be used with caution in patients with coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. Because of the known pharmacology of neostigmine methylsulfate as an acetylcholinesterase inhibitor, cardiovascular effects such as bradycardia, hypotension or dysrhythmia would be anticipated. In patients with certain cardiovascular conditions such as coronary artery disease, cardiac arrhythmias or recent acute coronary syndrome, the risk of blood pressure and heart rate complications may be increased. Risk of these complications may also be increased in patients with myasthenia gravis. Standard antagonism with anticholinergics (e.g., atropine) is generally successful to mitigate the risk of cardiovascular complications. 5.3. Hypersensitivity Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available. 5.4. Neuromuscular Dysfunction Large doses of Neostigmine Methylsulfate Injection, USP, administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of Neostigmine Methylsulfate Injection, USP, should be reduced if recovery from neuromuscular blockade is nearly complete. 5.5. Cholinergic Crisis It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of Neostigmine Methylsulfate Injection, USP. Both conditions result in extreme muscle weakness but require radically different treatment. [see OVERDOSAGE (10)]

6 ADVERSE REACTIONS 6.1. Clinical Trials 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. Adverse reactions to neostigmine methylsulfate are most often attributable to exaggerated pharmacological effects, in particular, at muscarinic receptor sites. The use of an anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, may prevent or mitigate these reactions. Quantitative adverse event data are available from trials of neostigmine methylsulfate in which 200 adult patients were exposed to the product. The following table lists the adverse reactions that occurred with an overall frequency of 1% or greater. 6.2. Post Marketing Experience The following adverse reactions have been identified during parenteral use of neostigmine methylsulfate. 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. ADVERSE 1 ADVERSE 2