NEOSTIGMINE METHYLSULFATE

Neostigmine methylsulfate, a cholinesterase inhibitor, is ( m -hydroxyphenyl) trimethyl ammonium methylsulfate dimethylcarbamate. The structural formula is: Neostigmine methylsulfate, USP is a white or almost white, crystalline powder (or) colorless crystals and is very soluble in water and soluble in alcohol. Neostigmine methylsulfate injection, USP is a sterile, nonpyrogenic clear colorless solution intended for intravenous use. Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate 0.5 mg, phenol (as liquefied phenol) 4.5 mg (used as preservative) and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with glacial acetic acid/sodium hydroxide to achieve a value of 5.5. Each mL of the 1 mg/mL strength contains neostigmine methylsulfate 1 mg, phenol (as liquefied phenol) 4.5 mg (used as preservative), and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with glacial acetic acid/sodium hydroxide to achieve a value of 5.5. Chemical Structure

Neostigmine methylsulfate injection is a cholinesterase inhibitor indicated for the reversal of the effects of non-­depolarizing neuromuscular blocking agents after surgery. Neostigmine methylsulfate injection, a cholinesterase inhibitor, is indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery. ( 1 )

Should be administered by trained healthcare providers ( 2.1 ) Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when neostigmine methylsulfate injection should be initiated and if additional doses are needed ( 2.2 ) For reversal of NMBAs with shorter half-lives, when first twitch response is substantially greater than 10% of baseline, or when a second twitch is present: 0.03 mg/kg by intravenous route ( 2.2 ) For reversal of NMBAs with longer half-lives or when first twitch response is close to 10% of baseline: 0.07 mg/kg by intravenous route ( 2.2 ) Maximum total dosage is 0.07 mg/kg or up to a total of 5 mg (whichever is less) ( 2.2 ) An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with neostigmine methylsulfate injection ( 2.4 ) 2.1 Important Dosage Information Neostigmine methylsulfate injection should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses of neostigmine methylsulfate injection should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of neostigmine methylsulfate injection and should be used to determine the need for additional doses. Neostigmine methylsulfate injection is for intravenous use only and should be injected slowly over a period of at least 1 minute. The neostigmine methylsulfate injection dosage is weight-based [see Dosage and Administration (2.2) ]. Prior to neostigmine methylsulfate injection administration and until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Satisfactory recovery should be judged by adequacy of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation. An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with neostigmine methylsulfate injection [see Dosage and Administration (2.4) ]. 2.2 Dosage in Adults a. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using neostigmine methylsulfate injection. b. There must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level, i.e., the response prior to NMBA administration, prior to the administration of neostigmine methylsulfate injection. c. Prior to administration, visually inspect neostigmine methylsulfate injection for particulate matter and discoloration. d. Neostigmine methylsulfate injection should be injected slowly by intravenous route over a period of at least 1 minute. e. A 0.03 mg/kg to 0.07 mg/kg dose of neostigmine methylsulfate injection will generally achieve a TOF twitch ratio of 90% (TOF 0.9 ) within 10 to 20 minutes of administration. Dose selection should be based on the extent of spontaneous recovery that has occurred at the time of administration, the half-life of the NMBA being reversed, and whether there is a need to rapidly reverse the NMBA. The 0.03 mg/kg dose is recommended for: Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or When the first twitch response to the TOF stimulus is substantially greater than 10% of baseline or when a second twitch is present. The 0.07 mg/kg dose is recommended for: NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or There is need for more rapid recovery. f. TOF monitoring should continue to be used to evaluate the extent of recovery of neuromuscular function and the possible need for an additional dose of neostigmine methylsulfate injection. g. TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to adequately ventilate and maintain a patent airway following tracheal extubation. h. Patients should continue to be monitored for adequacy of reversal from NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used. i. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less. 2.3 Dosage in Pediatric Patients, including Neonates Adult guidelines should be followed when neostigmine methylsulfate injection is administered to pediatric patients. Pediatric patients require neostigmine methylsulfate injection doses similar to those for adult patients. 2.4 Anticholinergic (Atropine or Glycopyrrolate) Administration An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with neostigmine methylsulfate injection. The anticholinergic agent should be administered intravenously using a separate syringe. In the presence of bradycardia, it is recommended that the anticholinergic agent be administered prior to neostigmine methylsulfate injection.

Neostigmine methylsulfate injection is contraindicated in patients with: known hypersensitivity to neostigmine methylsulfate (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis). peritonitis or mechanical obstruction of the intestinal or urinary tract. Hypersensitivity to neostigmine ( 4 ) Peritonitis or mechanical obstruction of the intestinal or urinary tract ( 4 )

Most common adverse reactions during treatment: bradycardia, nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eugia US LLC at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. System Organ Class Adverse Reaction Cardiovascular Disorders bradycardia, hypotension, tachycardia/heart rate increase Gastrointestinal Disorders dry mouth, nausea, post-procedural nausea, vomiting General Disorders and Administration Site Conditions incision site complication, pharyngolaryngeal pain, procedural complication, procedural pain Nervous System Disorders dizziness, headache, postoperative shivering, prolonged neuromuscular blockade Psychiatric Disorders insomnia Respiratory, Thoracic and Mediastinal Disorders dyspnea, oxygen desaturation <90% Skin and Subcutaneous Tissue Disorders pruritus 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. System Organ Class Adverse Reaction Allergic Disorders allergic reactions, anaphylaxis Nervous System Disorders convulsions, drowsiness, dysarthria, fasciculation, loss of consciousness, miosis, visual changes Cardiovascular Disorders cardiac arrest, cardiac arrhythmias (A-V block, nodal rhythm), hypotension, nonspecific EKG changes, syncope Respiratory, Thoracic and Mediastinal Disorders bronchospasm; increased oral, pharyngeal and bronchial secretions; respiratory arrest; respiratory depression Skin and Sub-cutaneous Tissue Disorders rash, urticaria Gastrointestinal Disorders bowel cramps, diarrhea, flatulence, increased peristalsis Renal and Urinary Disorders urinary frequency Musculoskeletal and Connective Tissue Disorders arthralgia, muscle cramps, spasms, weakness Miscellaneous diaphoresis, flushing

The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Use with caution when using neostigmine methylsulfate with other drugs which may alter the activity of metabolizing enzymes or transporters.