Neostigmine methylsulfate

Neostigmine methylsulfate
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: Gloria Picoy [2]

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Overview

Neostigmine methylsulfate is a cholinesterase Inhibitor that is FDA approved for the treatment of {{{indication}}}. Common adverse reactions include hypotension, nausea and vomiting.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Symptomatic control of myasthenia gravis

• Dosage: 1 mL of the 1:2000 solution (0.5 mg) subcutaneously or intramuscularly.
• Subsequent doses should be based on the individual patient's response.
• In most patients, however, oral treatment with Neostigmine Bromide tablets, 15 mg each, is adequate for control of symptoms.

Prevention of postoperative distention and urinary retention

• Dosage: 0.25 mg subcutaneously or intramuscularly as soon as possible after operation
• Repeat every 4 to 6 hours for two or three days.

Treatment of postoperative distention

• Dosage: 1 mL of the 1:2000 solution (0.5 mg) subcutaneously or intramuscularly, as required.

Treatment of urinary retention

• Dosage: 1 mL of the 1:2000 solution (0.5 mg) subcutaneously or intramuscularly.
• If urination does not occur within an hour, the patient should be catheterized.
• After the patient has voided, or the bladder has been emptied, continue the 0.5 mg injections every three hours for at least 5 injections.

Reversal of Effects of Non-depolarizing Blocking Agents

• Dosage: 0.5 to 2 mg neostigmine methylsulfate injection given by slow intravenous injection, repeated as required.

• When Neostigmine Methylsulfate Injection is administered, it is recommended that atropine sulfate (0.6 to 1.2 mg) also be given intravenously using separate syringes.

• The optimum time for administration of the drug is during hyperventilation when the carbon dioxide level of the blood is low.
• It should never be administered in the presence of high concentrations of halothane or cyclopropane.
• In cardiac cases and severely ill patients, it is advisable to titrate the exact dose of Neostigmine Methylsulfate required, using a peripheral nerve stimulator device.
• In the presence of bradycardia, the pulse rate should be increased to about 80/minute with Atropine before administering Neostigmine.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

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

Non–Guideline-Supported Use

• Symptomatic control of myasthenia gravis
• Prevention of postoperative distention and urinary retention
• Treatment of postoperative distention
• Treatment of urinary retention
• Reversal of effects of non-depolarizing blocking agents
• Paralytic ileus

• In dose increments of 0.05 mg to a total dose of 0.75 mg or to the induction of passage of flatus

• To prolong postoperative peripheral block anesthesia

• Postoperative peripherally administration for analgesia

• Pseudo-obstruction of intestine

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Neostigmine methylsulfate FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

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

Non–Guideline-Supported Use

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

Contraindications

• Patients with known hypersensitivity to the drug.
• Patients with peritonitis or mechanical obstruction of the intestinal or urinary tract.

Warnings

• Should be used with caution in patients with epilepsy, bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias or peptic ulcer.
• When large doses of Neostigmine are administered, the prior or simultaneous injection of Atropine Sulfate may be advisable. Separate syringes should be used for the Neostigmine and Atropine. Because of the possibility of hypersensitivity in an occasional patient, Atropine and anti-shock medication should always be readily available.

Adverse Reactions

Clinical Trials Experience

Side effects are generally due to an exaggeration of pharmacological effects of which salivation and fasciculation are the most common. Bowel cramps and diarrhea may also occur.

The following additional adverse reactions have been reported following the use of either Neostigmine Bromide or Neostigmine Methylsulfate.

• Allergic: Allergic reactions and anaphylaxis.

• Neurologic: Dizziness, convulsions, loss of consciousness, drowsiness, headache, dysarthria, miosis and visual changes.

• Cardiovascular: Cardiac arrhythmias (including bradycardia, tachycardia, A-V block and nodal rhythm) and nonspecific EKG changes have been reported, as well as cardiac arrest, syncope and hypotension. These have been predominantly noted following the use of the injectable form of neostigmine methylsulfate.

• Respiratory: Increased oral, pharyngeal and bronchial secretions, dyspnea, respiratory depression, respiratory arrest and bronchospasm.

• Dermatologic: Rash and urticaria.

• Gastrointestinal: Nausea, emesis, flatulence and increased peristalsis.

• Genitourinary: Urinary frequency.

• Musculoskeletal: Muscle cramps and spasms, arthralgia.

• Miscellaneous: Diaphoresis, flushing and weakness.

Postmarketing Experience

There is limited information regarding Neostigmine methylsulfate Postmarketing Experience in the drug label.

Drug Interactions

• Neostigmine methylsulfate injection does not antagonize, and may in fact prolong, the Phase 1 block of depolarizing muscle relaxants such as succinylcholine or decamethonium.
• Certain antibiotics, especially neomycin, streptomycin and kanamycin, have a mild but definite nondepolarizing blocking action which may accentuate neuromuscular block.
• These antibiotics should be used in the myasthenic patient only where definitely indicated, and then careful adjustment should be made of the anticholinesterase dosage.
• Local and some general anesthetics, antiarrhythmic agents and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all, in patients with myasthenia gravis; the dose of neostigmine methylsulfate may have to be increased accordingly.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C There are no adequate or well-controlled studies of Neostigmine Methylsulfate in either laboratory animals or in pregnant women. It is not known whether Neostigmine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Neostigmine Methylsulfate Injection, USP should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS): B2 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Neostigmine methylsulfate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Neostigmine methylsulfate during labor and delivery.

Nursing Mothers

It is not known whether neostigmine methylsulfate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Neostigmine Methylsulfate in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Pediatric Use

Safety and effectiveness in children have not been established.

Geriatic Use

There is no FDA guidance on the use of Neostigmine methylsulfate in geriatric settings.

Gender

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

Race

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

Renal Impairment

There is no FDA guidance on the use of Neostigmine methylsulfate in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Neostigmine methylsulfate in patients with hepatic impairment.

Females of Reproductive Potential and Males

Studies on the effect of neostigmine methylsulfate on fertility and reproduction have not been performed.

Immunocompromised Patients

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

Administration and Monitoring

Administration

Intravenous

Monitoring

Only in exceptional cases should the total dose of Neostigmine Methylsulfate exceed 5 mg. It is recommended that the patient be well ventilated and a patent airway maintained until complete recovery of normal respiration is assured.

IV Compatibility

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

Overdosage

Overdosage of neostigmine methylsulfate 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 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 judgement. 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 abolish or minimize gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.

The LD50 of neostigmine methylsulfate in mice is 0.3 ± 0.02 mg/kg intravenously, 0.54 ± 0.03 mg/kg subcutaneously and 0.395 ± 0.025 mg/kg intramuscularly; in rats the LD50 is 0.315 ± 0.019 mg/kg intravenously, 0.445 ± 0.032 mg/kg subcutaneously and 0.423 ± 0.032 mg/kg intramuscularly.

Pharmacology

Neostigmine methylsulfate
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	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
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 inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission.

Structure

Neostigmine methylsulfate is the dimethylcarbamate of (m-hydroxyphenyl) trimethylammonium methylsulfate. The structural formula is:

Pharmacodynamics

It enhances cholinergic action by facilitating the transmission of impulses across neuromuscular junctions. It also has a direct cholinomimetic effect on skeletal muscle and possibly on autonomic ganglion cells and neurons of the central nervous system. Neostigmine undergoes hydrolysis by cholinesterase and is also metabolized by microsomal enzymes in the liver. Protein binding to human serum albumin ranges from 15 to 25 percent.

Pharmacokinetics

Following intramuscular administration, Neostigmine is rapidly absorbed and eliminated. In a study of five patients with myasthenia gravis, peak plasma levels were observed at 30 minutes, and the half-life ranged from 51 to 90 minutes. Approximately 80 percent of the drug was eliminated in urine within 24 hours; approximately 50% as the unchanged drug and 30 percent as metabolites. Following intravenous administration, plasma half-life ranges from 47 to 60 minutes have been reported with a mean half-life of 53 minutes.

The clinical effects of Neostigmine usually begin within 20 to 30 minutes after intramuscular injection and last from 2.5 to 4 hours.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis

There have been no studies with Neostigmine Methylsulfate which would permit an evaluation of its carcinogenic or mutagenic potential

Nonteratogenic Effects

Anticholinesterase drugs may cause uterine irritability and induce premature labor when given intravenously to pregnant women near term.

Clinical Studies

There is limited information regarding Neostigmine methylsulfate Clinical Studies in the drug label.

How Supplied

• Neostigmine Methylsulfate Injection (1 mg/mL)

• NDC 0517-0033-25
• 10 mL Multiple Dose Vials
• Boxes of 25

• Neostigmine Methylsulfate Injection (0.5 mg/mL)

• NDC 0517-0034-25
• 10 mL Multiple Dose Vials
• Boxes of 25

Storage

Store at 20° to 25°C (68° to 77°F)

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

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

Precautions with Alcohol

Alcohol-Neostigmine methylsulfate 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 methylsulfate 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.

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