FDA

Neostigmine Methylsulfate

Approved 10 Jul 2018IntravenousSolution

The FDA lists this product in 39 strengths and forms.

Indications

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) .

Contraindications

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)

Warnings and precautions

Bradycardia: Atropine or glycopyrrolate should be administered prior to neostigmine methylsulfate injection to lessen risk of bradycardia. ( 5.1 )
Serious Reactions with Coexisting Conditions: Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. ( 5.2 )
Neuromuscular Dysfunction: Can occur if large doses of neostigmine methylsulfate injection are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. ( 5.4 ) 5.1. Bradycardia Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to neostigmine methylsulfate injection to lessen the risk of bradycardia [see Dosage and Administration ( 2.4) ]. 5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions Neostigmine methylsulfate injection 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. 5.3. Hypersensitivity Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available. 5.4. Neuromuscular Dysfunction Large doses of neostigmine methylsulfate injection administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of neostigmine methylsulfate injection should be reduced if recovery from neuromuscular blockade is nearly complete. 5.5. Cholinergic Crisis It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine methylsulfate injection. Both conditions result in extreme muscle weakness but require radically different treatment. [see Overdosage ( 10 )]

Indications

Contraindications

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)

Warnings and precautions

Bradycardia: Atropine or glycopyrrolate should be administered prior to neostigmine methylsulfate injection to lessen risk of bradycardia. ( 5.1 )
Serious Reactions with Coexisting Conditions: Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. ( 5.2 )
Neuromuscular Dysfunction: Can occur if large doses of neostigmine methylsulfate injection are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. ( 5.4 ) 5.1. Bradycardia Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to neostigmine methylsulfate injection to lessen the risk of bradycardia [see Dosage and Administration ( 2.4) ]. 5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions Neostigmine methylsulfate injection 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. 5.3. Hypersensitivity Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available. 5.4. Neuromuscular Dysfunction Large doses of neostigmine methylsulfate injection administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of neostigmine methylsulfate injection should be reduced if recovery from neuromuscular blockade is nearly complete. 5.5. Cholinergic Crisis It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine methylsulfate injection. Both conditions result in extreme muscle weakness but require radically different treatment. [see Overdosage ( 10 )]

Pregnancy and breastfeeding

8.1Pregnancy 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 (0.1 to 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 basis) of 1.6, 4 and 8.1 mcg/kg/day and 3.2, 8.1, and 13 mcg/kg/day, respectively, during the period of organogenesis (Gestation Days 6 through 17 for rats and Gestation Days 6 through 18 for rabbits).

There was no evidence for a teratogenic effect in rats and rabbits up to HED 8.1 and 13 mcg/kg/day, which are approximately 0.097-times and 0.16-times the MRHD of 5 mg/60 kg, respectively in the presence of minimal maternal toxicity (tremors, ataxia, and prostration). The studies resulted in exposures in the animals well below predicted exposures in humans. In a pre- and postnatal development study in rats, neostigmine methylsulfate was administered to pregnant female rats at human equivalent doses (HED) of 1.6, 4 and 8.1 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 to 8.1 mcg/kg/day which is 0.097-times the MRHD of 5 mg/60 kg on a mg/m 2 basis in the presence of minimal maternal toxicity (tremors, ataxia, and prostration). The studies resulted in exposures in the animals well below predicted exposures in humans.

Adverse reactions

Most common adverse reactions during treatment: bradycardia, nausea and vomiting ( 6) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy's Laboratories Inc., at 1-888-375-3784 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 e 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

Neostigmine Methylsulfate

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Neostigmine Methylsulfate

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

Composition

Strengths and forms

Official product information

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