NEOSTIGMINE METHYLSULFATE- neostigmine methylsulfate_injection

Neostigmine methylsulfate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, neostigmine methylsulfate induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as nondepolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade. Neostigmine methylsulfate-induced increases in acetylcholine levels results in the potentiation of both muscarinic and nicotinic cholinergic activity. The resulting elevation of acetylcholine competes with nondepolarizing neuromuscular blocking agents to reverse neuromuscular blockade. Neostigmine methylsulfate does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system. Distribution: Metabolism: Elimination: Renal impairment: Hepatic impairment: Pediatrics: Drug Interaction Studies:.

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) 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. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using Neostigmine Methylsulfate Injection. 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. An anticholinergic agent, e. , 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.

Most common adverse reactions during treatment: bradycardia, nausea and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact XIROMED LLC at 1-844-XIROMED (844-947-6633) or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. , 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 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 Cardiovascular Disorders cardiac arrest, cardiac arrhythmias (A-V block, nodal rhythm), 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.

Neostigmine Methylsulfate Injection is contraindicated in patients with: Hypersensitivity to neostigmine (4).

Pregnancy: No human data and limited animal data exist. Use only if clearly needed. Risk Summary There are no adequate or well-controlled studies of Neostigmine Methylsulfate Injection in pregnant women. It is not known whether Neostigmine Methylsulfate Injection can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. The incidence of malformations in human pregnancies has not been established for neostigmine as the data are limited. All pregnancies, regardless of drug exposure, have a background risk of 2 to 4% for major birth defects, and 15 to 20% for pregnancy loss. No adverse effects were noted in rats or rabbits treated with human equivalent doses of neostigmine methylsulfate doses up to 8. 1 and 13 mcg/kg/day, respectively, during organogenesis (0. 2-times the maximum recommended human dose of 5 mg/60 kg person/day based on body surface area comparisons). Anticholinesterase drugs, including neostigmine may cause uterine irritability and induce premature labor when administered to pregnant women near term. Neostigmine Methylsulfate Injection should be given to a pregnant woman only if clearly needed. Data Animal Data In embryofetal development studies, rats and rabbits were administered neostigmine methylsulfate at human equivalent doses (HED, on a mg/m 2 In a pre- and postnatal development study in rats, neostigmine methylsulfate was administered to pregnant female rats at human equivalent doses (HED) of 1. 1 mcg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21. There were no adverse effects on physical development, behavior, learning ability, or fertility in the offspring occurred at HED doses up 8. 1 mcg/kg/day which is 0. 097-times the MRHD of 5 mg/60 kg on a mg/m 2 The effect of Neostigmine Methylsulfate Injection on the mother and fetus with regard to labor, delivery, the need for forceps delivery or other intervention or resuscitation of the newborn, is not known. Cholinesterase inhibitor drugs may induce premature labor when given intravenously to pregnant women near term. It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when Neostigmine Methylsulfate Injection is administered to a nursing woman. Neostigmine Methylsulfate Injection is approved for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery in pediatric patients of all ages. Recovery of neuromuscular activity occurs more rapidly with smaller doses of cholinesterase inhibitors in infants and children than in adults. However, infants and small children may be at greater risk of complications from incomplete reversal of neuromuscular blockade due to decreased respiratory reserve. The risks associated with incomplete reversal outweigh any risk from giving higher doses of Neostigmine Methylsulfate Injection (up to 0. 07 mg/kg or up to a total of 5 mg, whichever is less). The dose of Neostigmine Methylsulfate Injection required to reverse neuromuscular blockade in children varies between 0. 07 mg/kg, the same dose range shown to be effective in adults, and should be selected using the same criteria as used for adult patients. [see Clinical Pharmacology (12. 3)] Since the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate, the effects of an anticholinergic agent (e. , atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension. Because elderly patients are more likely to have decreased renal function, Neostigmine Methylsulfate Injection should be used with caution and monitored for a longer period in elderly patients. The duration of action of neostigmine methylsulfate is prolonged in the elderly; however, elderly patients also experience slower spontaneous recovery from neuromuscular blocking agents. Therefore, dosage adjustments are not generally needed in geriatric patients; however, they should be monitored for longer periods than younger adults to assure additional doses of Neostigmine Methylsulfate Injection are not required. The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient. [see Dosage and Administration (2. Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects. Although no adjustments to Neostigmine Methylsulfate Injection dosing appear to be warranted in patients with impaired renal function, they should be closely monitored to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of Neostigmine Methylsulfate Injection. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended. The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment have not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. No adjustments to the dosing of Neostigmine Methylsulfate Injection appear to be warranted in patients with hepatic insufficiency. However, patients should be carefully monitored if hepatically cleared neuromuscular blocking agents were used during their surgical procedure as their duration of action may be prolonged by hepatic insufficiency whereas Neostigmine Methylsulfate Injection, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of Neostigmine Methylsulfate Injection. This same situation may arise if the neuromuscular blocking agent has active metabolites.

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 Injection with other drugs which may alter the activity of metabolizing enzymes or transporters.

OVERDOSAGE
Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of Neostigmine Methylsulfate Injection (cholinergic crisis), but may be managed by the use of additional atropine or glycopyrrolate. The possibility of iatrogenic overdose can be lessened by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored. Overdosage of Neostigmine Methylsulfate Injection can cause cholinergic crisis, which is characterized by increasing muscle weakness, and through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish from cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of Neostigmine Methylsulfate Injection or other drugs in this class, in the presence of cholinergic crisis or of a refractory or “insensitive” state, could have grave consequences. The two types of crises may be differentiated by the use of edrophonium chloride as well as by clinical judgment. Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is also recommended. Atropine may also be used to lessen gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.
NONCLINICAL TOXICOLOGY
Carcinogenesis: Genotoxicity: Impairment of Fertility:
CLINICAL STUDIES
The evidence for the efficacy of neostigmine methylsulfate for the reversal of the effects of non­ depolarizing neuromuscular blocking agents after surgery is derived from the published literature. Randomized, spontaneous-recovery or placebo-controlled studies using similar efficacy endpoints evaluated a total of 404 adult and 80 pediatric patients undergoing various surgical procedures. Patients had reductions in their recovery time from neuromuscular blockade with neostigmine methylsulfate treatment compared to spontaneous recovery.

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