NEOSTIGMINE METHYLSULFATE

Neostigmine Methylsulfate Injection, USP, a cholinesterase inhibitor, has an empirical formula of C 13 H 22 N 2 O 6 S, a molecular weight of 334.39 g/mol and the following structural formula: Neostigmine Methylsulfate Injection is formulated with neostigmine methylsulfate, a white crystalline powder, chemically designated as (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. Neostigmine Methylsulfate Injection, USP is available in two dosage strengths; 0.5 mg/mL, and 1 mg/mL in 10 mL multiple dose amber glass vials. The composition per mL is as follows: Ingredients mg/mL Neostigmine Methylsulfate 0.5 1 Phenol (as Liquefied Phenol, USP) 4.5 4.5 Sodium Acetate, USP (Trihydrate) 0.2 0.2 Water for Injection q.s. q.s Phenol is added as a preservative. Acetic acid and/or sodium hydroxide may have been added for pH adjustment. structure

Neostigmine Methylsulfate Injection, a cholinesterase inhibitor, is indicated for reversal of the effects of nondepolarizing neuromuscular blocking agents (NMBA) after surgery. Neostigmine Methylsulfate, a cholinesterase inhibitor, is indicated for reversal of the effects of nondepolarizing neuromuscular blocking agents (NMBA) after surgery ( 1 ).

Dosage Should be administered by trained healthcare providers ( 2.1 ) Recommend use of a peripheral nerve stimulator to determine whether neostigmine methylsulfate should be administered and to monitor recovery from neuromuscular blockade ( 2.1 ). Recommended dosage range is 0.03 mg/kg to 0.07mg/kg for reversing nondepolarizing neuromuscular block when administered with an anticholinergic agent (atropine or glycopyrrolate) ( 2.2 , 2.3 , 2.4 ) 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 ( 2.4 ) Dose of Anticholinergic Agent (atropine or glycopyrrolate) Administer atropine sulfate (~15 mcg/kg) or glycopyrrolate (~10 mcg/kg) intravenously either several minutes before or concomitantly with neostigmine methylsulfate (using separate syringes) ( 2.4 ) 2.1 Important Dosage and Administration Instructions Neostigmine 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. Prior to Neostigmine Methylsulfate Injection administration and up until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Use a peripheral nerve stimulator capable of delivering a train-of-four (TOF) stimulus to evaluate the extent of recovery of neuromuscular function, and to determine the time of the first dose and the need for additional doses of Neostigmine Methylsulfate Injection. Prior to the administration of Neostigmine Methylsulfate Injection, 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). Dose selection should be based on the extent of spontaneous recovery at time of injection, half-life of the neuromuscular blocking agent (NMBA) to be reversed, and need for rapid NMBA reversal. Patients should continue to be monitored for adequacy of reversal of the effect of 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. Neostigmine Methylsulfate Injection is administered by intravenous bolus injection. Additional, carefully adjusted bolus doses are administered according to the patient’s response. An anticholinergic agent (e.g., atropine or glycopyrrolate) should be administered prior to or concomitantly with Neostigmine Methylsulfate Injection [ see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.5 ) ]. TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade. Satisfactory recovery should be judged by the patient’s ability to maintain a patent airway, adequacy of ventilation, and skeletal muscle tone. 2.2 Recommended Dosage in Adults The recommended dose range of Neostigmine Methylsulfate Injection is 0.03 mg/kg to 0.07 mg/kg administered as an intravenous bolus. A dose less than 0.04 mg/kg is recommended for reversal of the effect 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. A dose of 0.07 mg/kg is recommended for the reversal of the effect of NMBAs with longer half-lives (e.g., vecuronium or pancuronium), or when first twitch response is not substantially greater than 10% of baseline, or if there is need for more rapid recovery. Additional doses may be required. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less. 2.3 Recommended 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 Concomitant or Pre-Administration of Anticholinergic Agents An anticholinergic agent (e.g., atropine sulfate or glycopyrrolate) should be administered intravenously several minutes prior to or with Neostigmine Methylsulfate Injection administration using separate syringes. For bradycardic patients, the anticholinergic agent should be administered prior to Neostigmine Methylsulfate Injection. 2.1 Important Dosage and Administration Instructions Neostigmine 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. Prior to Neostigmine Methylsulfate Injection administration and up until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Use a peripheral nerve stimulator capable of delivering a train-of-four (TOF) stimulus to evaluate the extent of recovery of neuromuscular function, and to determine the time of the first dose and the need for additional doses of Neostigmine Methylsulfate Injection. Prior to the administration of Neostigmine Methylsulfate Injection, 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). Dose selection should be based on the extent of spontaneous recovery at time of injection, half-life of the neuromuscular blocking agent (NMBA) to be reversed, and need for rapid NMBA reversal. Patients should continue to be monitored for adequacy of reversal of the effect of 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. Neostigmine Methylsulfate Injection is administered by intravenous bolus injection. Additional, carefully adjusted bolus doses are administered according to the patient’s response. An anticholinergic agent (e.g., atropine or glycopyrrolate) should be administered prior to or concomitantly with Neostigmine Methylsulfate Injection [ see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.5 ) ]. TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade. Satisfactory recovery should be judged by the patient’s ability to maintain a patent airway, adequacy of ventilation, and skeletal muscle tone. 2.2 Recommended Dosage in Adults The recommended dose range of Neostigmine Methylsulfate Injection is 0.03 mg/kg to 0.07 mg/kg administered as an intravenous bolus. A dose less than 0.04 mg/kg is recommended for reversal of the effect 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. A dose of 0.07 mg/kg is recommended for the reversal of the effect of NMBAs with longer half-lives (e.g., vecuronium or pancuronium), or when first twitch response is not substantially greater than 10% of baseline, or if there is need for more rapid recovery. Additional doses may be required. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less. 2.3 Recommended 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 Concomitant or Pre-Administration of Anticholinergic Agents An anticholinergic agent (e.g., atropine sulfate or glycopyrrolate) should be administered intravenously several minutes prior to or with Neostigmine Methylsulfate Injection administration using separate syringes. For bradycardic patients, the anticholinergic agent should be administered prior to Neostigmine Methylsulfate Injection.

Neostigmine 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 urinary or intestinal tracts. Hypersensitivity to neostigmine ( 4 ) Peritonitis or mechanical obstruction of urinary or intestinal tracts ( 4 )

The most common adverse reactions include bradycardia and nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial 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. The following serious adverse reactions are described below and elsewhere in the labeling: Bradycardia [ see Warnings and Precautions ( 5.1 ) ] Cardiovascular Complications [ see Warnings and Precautions ( 5.2 ) ] Hypersensitivity (Anaphylaxis) [ see Warnings and Precautions ( 5.3 ) ] 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. Adverse reactions that occurred with an overall frequency of 1% or greater included the following: Allergic: Allergic reactions and anaphylaxis. Neurological: Dizziness, syncope, weakness, convulsions, loss of consciousness, drowsiness, headache, dysarthria, miosis and visual changes. Cardiovascular: Cardiac arrhythmias including bradycardia, tachycardia, atrioventricular block and nodal rhythm, as well as cardiac arrest, and hypotension. Respiratory: Increased oral, pharyngeal and bronchial secretions, dyspnea, respiratory depression, oxygen desaturation, respiratory arrest and bronchospasm. Dermatologic: Diaphoresis, flushing, rash, pruritus, and urticaria. Gastrointestinal: Dry mouth, nausea, emesis, flatulence and increased peristalsis. Genitourinary: Increased urinary frequency. Musculoskeletal: Muscle cramps and spasm, arthralgia. Psychiatric: Insomnia General: Incision site complication, pharyngolaryngeal pain, procedural complication, procedural pain 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. 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 Subcutaneous Tissue Disorders: Rash, urticaria diaphoresis, flushing Gastrointestinal Disorders: Bowel cramps, diarrhea, flatulence, increased peristalsis Renal and Urinary Disorders: Urinary frequency Musculoskeletal and Connective Tissue Disorders: Arthralgia, muscle cramps, spasms, weakness

The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Closely monitor patients for a longer period of time when using Neostigmine Methylsulfate Injection with other drugs which may alter the activity of metabolizing enzymes or transporters. 7.1 Depolarizing Muscle relaxants Use of neostigmine to reverse the effects of depolarizing muscle relaxants such as succinylcholine is not recommended, because it may prolong the phase-1 block. 7.2 Antibiotics Certain antibiotics, particularly neomycin, streptomycin and kanamycin have nondepolarizing neuromuscular blocking action, and therefore, neostigmine dose adjustments may be required to reverse neuromuscular block in patients who have been taking these drugs. There was no effect on neostigmine action on rocuronium reversal by cefuroxime, metronidazole, cefuroxime or metronidazole.