Neostigmine

Jump to: navigation, search
Neostigmine
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Overview

Neostigmine is an antidote, cholinergic cholinesterase inhibitor and autonomic central nervous system agent that is FDA approved for the treatment of the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. Common adverse reactions include hypotension, nausea and vomiting.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

  • BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.

Dosing Information

Important Dosage Information
  • BLOXIVERZ 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 BLOXIVERZ should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of BLOXIVERZ and should be used to determine the need for additional doses.
  • BLOXIVERZ is for intravenous use only and should be injected slowly over a period of at least 1 minute. The BLOXIVERZ dosage is weight-based [see Dosage and Administration (2.2)].
  • Prior to BLOXIVERZ 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 BLOXIVERZ [see Dosage and Administration (2.4)]
Dosage in Adults
  • Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using BLOXIVERZ.
  • 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 BLOXIVERZ.
  • Prior to administration, visually inspect BLOXIVERZ for particulate matter and discoloration.
  • BLOXIVERZ should be injected slowly by intravenous route over a period of at least 1 minute.
  • A 0.03 mg/kg to 0.07 mg/kg dose of BLOXIVERZ will generally achieve a TOF twitch ratio of 90% (TOF0.9) 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.
  • 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 BLOXIVERZ.
  • 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.
  • 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.

The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less.

Anticholinergic (Atropine or Glycopyrrolate) Administration
  • An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ. 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 BLOXIVERZ.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Neostigmine in adult patients.

Non–Guideline-Supported Use

  • Myasthenia gravis, When oral therapy is impractical
  • Paralytic ileus - Postoperative complication

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

  • BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.

Dosing Information

Dosage in Pediatric Patients, including Neonates
  • Adult guidelines should be followed when BLOXIVERZ is administered to pediatric patients. Pediatric patients require BLOXIVERZ doses similar to those for adult patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Neostigmine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Neostigmine in pediatric patients.

Contraindications

  • BLOXIVERZ 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).
  • With peritonitis or mechanical obstruction of the intestinal or urinary tract.

Warnings

Bradycardia
  • Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to BLOXIVERZ to lessen the risk of bradycardia.
Serious Adverse Reactions in Patients with Certain Coexisting Conditions
  • BLOXIVERZ 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.
Hypersensitivity
  • Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available.
Neuromuscular Dysfunction
  • Large doses of BLOXIVERZ administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of BLOXIVERZ should be reduced if recovery from neuromuscular blockade is nearly complete.
Cholinergic Crisis
  • It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of BLOXIVERZ. Both conditions result in extreme muscle weakness but require radically different treatment.

Adverse Reactions

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.
This image is provided by the National Library of Medicine.

Postmarketing 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.
This image is provided by the National Library of Medicine.

Drug Interactions

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

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C

  • It is not known whether neostigmine methylsulfate can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. BLOXIVERZ should be given to a pregnant woman only if clearly needed.
  • Animal reproduction studies have not been conducted with neostigmine methylsulfate.


Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Neostigmine in women who are pregnant.

Labor and Delivery

  • The effect of BLOXIVERZ 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.

Nursing Mothers

  • It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when BLOXIVERZ is administered to a nursing woman.

Pediatric Use

  • BLOXIVERZ 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 BLOXIVERZ (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less).
  • The dose of BLOXIVERZ required to reverse neuromuscular blockade in children varies between 0.03 mg - 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.g., atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension.

Geriatic Use

  • Because elderly patients are more likely to have decreased renal function, BLOXIVERZ 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 BLOXIVERZ are not required. The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient.

Gender

There is no FDA guidance on the use of Neostigmine with respect to specific gender populations.

Race

There is no FDA guidance on the use of Neostigmine with respect to specific racial populations.

Renal Impairment

  • Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects.
  • Although no adjustments to BLOXIVERZ 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 BLOXIVERZ. 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.

Hepatic Impairment

  • 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 BLOXIVERZ 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 BLOXIVERZ, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of BLOXIVERZ. This same situation may arise if the neuromuscular blocking agent has active metabolites. 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.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Neostigmine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Neostigmine in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Intravenous

Monitoring

There is limited information regarding Neostigmine Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Neostigmine and IV administrations.

Overdosage

  • Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of BLOXIVERZ (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 BLOXIVERZ 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 BLOXIVERZ 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.

Pharmacology

Neostigmine Ion V.1.png
Neostigmine ball-and-stick.png
Neostigmine
Systematic (IUPAC) name
3-{[(dimethylamino)carbonyl]oxy}-N,N,N-trimethylbenzenaminium
Identifiers
CAS number 59-99-4
ATC code N07AA01 S01EB06 (WHO) Template:ATCvet
PubChem 4456
DrugBank DB01400
Chemical data
Formula C12H19N2O2 
Mol. mass 223.294 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability Unclear, probably less than 5%
Metabolism Slow hydrolysis by acetylcholinesterase and also by plasma esterases
Half life 50–90 minutes
Excretion Unchanged drug (up to 70%) and alcoholic metabolite (30%) are excreted in the urine
Therapeutic considerations
Pregnancy cat.

?

Legal status
Routes ?

Mechanism of Action

  • 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.

Structure

  • Neostigmine methylsulfate, a cholinesterase inhibitor, is (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is:
This image is provided by the National Library of Medicine.
  • Neostigmine methylsulfate is a white crystalline powder and is very soluble in water and soluble in alcohol. BLOXIVERZ is a sterile, nonpyrogenic solution intended for intravenous use.
  • Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate 0.5 mg, 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 acetic acid/sodium hydroxide to a value of 5.5.
  • Each mL of the 1 mg/mL strength contains neostigmine methylsulfate 1 mg, 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 acetic acid/sodium hydroxide to achieve a value of 5.5.

Pharmacodynamics

  • 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.

Pharmacokinetics

Distribution:
  • Following intravenous injection, the observed neostigmine methylsulfate volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of neostigmine methylsulfate to human serum albumin ranges from 15 to 25%.
Metabolism:
  • Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver.
Elimination:
  • Following intravenous injection, the reported elimination half-life of neostigmine methylsulfate is between 24 and 113 minutes. Total body clearance of neostigmine methylsulfate is reported between 1.14 and 16.7 mL/min/kg.
Renal impairment:
  • Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects; elimination half-life for normal, transplant and anephric patients were 79.8 ± 48.6, 104.7 ± 64 and 181 ± 54 min (mean ± SD), respectively.
Hepatic impairment:
  • The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment has not been studied.
Pediatrics:
  • Elimination half-life of neostigmine methylsulfate in infants (2-10 months), children (1-6 years) and adults (29-48 years) were 39 ± 5 min, 48 ± 16 min, and 67 ± 8 min (mean ± SD), respectively. Observed neostigmine methylsulfate clearance for infants, children and adults were 14 ± 3, 11 ± 3 and 10 ± 2 mL/min/kg (mean ± SD), respectively.
Drug Interaction Studies:
  • The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:
  • Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine.
Genotoxicity:
  • Neostigmine methylsulfate was not mutagenic or clastogenic when evaluated in an in vitro bacterial reverse mutation assay (Ames test), an in vitro Chinese hamster ovary cell chromosomal aberration assay, or an in vivo mouse bone marrow micronucleus assay.
Impairment of Fertility:
  • Studies on the effect of neostigmine methylsulfate on fertility have not been performed.

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.

How Supplied

  • BLOXIVERZ (Neostigmine Methylsulfate Injection, USP) is available in the following:
This image is provided by the National Library of Medicine.

The vial stopper is not made with natural rubber latex.

Manufactured for:

Éclat Pharmaceuticals

Chesterfield, MO 63005 USA

Storage

  • BLOXIVERZ should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
  • Protect from light. Store in carton until time of use.

Images

Drug Images

Package and Label Display Panel

Package Label - Principal Display Panel - Neostigmine Methylsulfate - 0.5 mg Vial - NDC 76014-002-33
This image is provided by the National Library of Medicine.
Package Label - Principal Display Panel - Neostigmine Methylsulfate - 0.5 mg Carton - NDC 76014-002-33
This image is provided by the National Library of Medicine.
Package Label - Principal Display Panel - Neostigmine Methylsulfate – 0.5 mg Ten Carton Package Flat Label - NDC 76014-002-10
This image is provided by the National Library of Medicine.
Package Label - Principal Display Panel - Neostigmine Methylsulfate – 0.5 mg Ten Carton Package ECL - NDC 76014-002-10
This image is provided by the National Library of Medicine.
Package Label - Principal Display Panel - Neostigmine Methylsulfate - 1.0 mg Vial - NDC 76014-003-33
This image is provided by the National Library of Medicine.
Package Label - Principal Display Panel - Neostigmine Methylsulfate - 1.0 mg Carton - NDC 76014-003-33
This image is provided by the National Library of Medicine.
Package Label - Principal Display Panel - Neostigmine Methylsulfate – 1.0 mg Ten Carton Package Flat Label - NDC 76014-003-10
This image is provided by the National Library of Medicine.
Package Label - Principal Display Panel - Neostigmine Methylsulfate – 1.0 mg Ten Carton Package ECL - NDC 76014-003-10
This image is provided by the National Library of Medicine.

Patient Counseling Information

There is limited information regarding Neostigmine Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Neostigmine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

  • Bloxiverz

Look-Alike Drug Names

There is limited information regarding Neostigmine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


Linked-in.jpg