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Neostigmine

FDA Drug Information • Also known as: Neostigmine

Brand Names
Neostigmine
Route
INTRAVENOUS
Dosage Form
INJECTION
Product Type
HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION Neostigmine methylsulfate, a cholinesterase inhibitor, is (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is: Neostigmine methylsulfate is a white crystalline powder and is very soluble in water and soluble in alcohol. Neostigmine methylsulfate injection USP, 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 achieve a value of 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.

What Is Neostigmine Used For?

1 INDICATIONS AND USAGE 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) .

Dosage and Administration

2 DOSAGE AND ADMINISTRATION

  • Should be administered by trained healthcare providers ( 2.1)
  • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when neostigmine methylsulfate injection should be initiated and if additional doses are needed ( 2.2 )
  • 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 injection ( 2.4 ) 2.1. Important Dosage Information 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. Neostigmine methylsulfate injection is for intravenous use only and should be injected slowly over a period of at least 1 minute. The neostigmine methylsulfate injection dosage is weight-based [see Dosage and Administration ( 2.2) ]. Prior to neostigmine methylsulfate injection 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 neostigmine methylsulfate injection [see Dosage and Administration (2.4 )] 2.2. Dosage in Adults a. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using neostigmine methylsulfate injection. b. 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 neostigmine methylsulfate injection. c. Prior to administration, visually inspect neostigmine methylsulfate injection for particulate matter and discoloration. d. Neostigmine methylsulfate injection should be injected slowly by intravenous route over a period of at least 1 minute. e. A 0.03 mg/kg to 0.07 mg/kg dose of neostigmine methylsulfate injection will generally achieve a TOF twitch ratio of 90% (TOF0.9) within 10...

    • Side Effects (Adverse Reactions)

    6 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

    Drug Interactions

    7 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 neostigmine methylsulfate injection with other drugs which may alter the activity of metabolizing enzymes or transporters.

    Contraindications

    4 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)

    • Pregnancy and Breastfeeding

    8.1 Pregnancy 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...

    Overdosage

    10 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.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING Neostigmine methylsulfate injection, USP is available in the following: NDC No. Strength Vial Size 43598-528-11 0.5 mg/mL 10 mL multiple-dose vial individually packaged in a carton containing 1 vial 43598-529-11 1 mg/mL 10 mL multiple-dose vial individually packaged in a carton containing 1 vial 43598-528-36 0.5 mg/mL 10 mL multiple-dose vial packaged in a carton containing 10 vials 43598-529-36 1 mg/mL 10 mL multiple-dose vial packaged in a carton containing 10 vials The vial stopper is not made with natural rubber latex. Neostigmine methylsulfate injection, USP should be store at 20°C to 25°C (68°F to 77°F); (see USP Controlled Room Temperature). Protect from light. Store in carton until time of use. Rx Only Distributor: Dr. Reddy’s Laboratories Inc., Princeton, NJ 08540 Made in India Issued: 0221

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.