Class: Parasympathomimetic (Cholinergic) Agents
Note: This monograph also contains information on Neostigmine Methylsulfate
VA Class: AU300
CAS Number: 59-99-4
Brands: Prostigmin
Introduction
Reversible anticholinesterase agent.a b c
Uses for Neostigmine Bromide
Myasthenia Gravis
Symptomatic management of myasthenia gravis to improve muscle strength.a b c
Not effective in patients resistant to anticholinesterase drugs.a
Differential diagnosis of myasthenia gravis.a However, edrophonium is preferred except in lengthy procedures involving tests of limb strength.a
Surgery
Postoperative reversal of the effects of nondepolarizing neuromuscular blocking agents (e.g., tubocurarine, metocurine, gallamine [all no longer commercially available in the US], pancuronium).a b
Not effective and should not be used for reversal of depolarizing neuromuscular agents (e.g., succinylcholine, decamethonium).a
Postoperative Distention and Urinary Retention
Prevention and treatment of postoperative distention and urinary retention after excluding mechanical obstruction;a b bethanechol chloride usually preferred.a
Aminoglycoside Toxicity
Has been used to antagonize the neuromuscular blocking effects of aminoglycoside antibiotics† (e.g., kanamycin) with variable results; some clinicians found neostigmine ineffective.a (See Specific Drugs under Interactions.)
Acceleration of Barium Transit through Small Intestine
Has been used to accelerate barium transport through the small bowel†; other agents may be more effective.a
Neostigmine Bromide Dosage and Administration
General
Diagnosis of Myasthenia Gravis
Discontinue all anticholinesterase drugs for at least 8 hours before administering neostigmine methylsulfate.a
Administer atropine sulfate IM 30 minutes before or IV concurrently with IM neostigmine methylsulfate to prevent adverse muscarinic effects.a
Determine placebo response by measuring muscle strength in cranial musculature before and after atropine sulfate administration.a
Other myopathies may show slight improvement in muscle strength; however, only myasthenia gravis responds with marked improvement.a
Treatment of Myasthenia Gravis
Dosage, route, and frequency of administration depend on the requirements and clinical response of the patient.a Carefully individualize dosage according to individual requirements and response and minimize adverse effects by precise dosage adjustment.a
Use parenteral form if oral therapy is impracticalb or in acute myasthenic crisis if difficulty in breathing and swallowing is present.c Transfer to the oral formulation as soon as tolerated.c
Dosage requirements may vary from day to day, according to remissions and exacerbations of the disease and the physical and emotional stress suffered by the patient.a
Treat mild exacerbations by increasing dosage under medical supervision as long as increase produces symptomatic improvement.a
Complete restoration of muscle strength is rare; do not attempt to relieve all symptoms by increasing dosage above maximum response level.a
Once stabilized on neostigmine, may teach patients how to recognize adverse muscarinic effects and self-modify dosage or take atropine, if necessary.a
Individual muscle groups respond differently to the same dose; may produce weakness in one while increasing strength in another.a Measure vital capacity whenever increasing dosage to ensure good respiratory function.a Have adequate facilities for CPR, cardiac monitoring, endotracheal intubation, and respiratory assistance available during dosage adjustment.a
Patients may become refractory after prolonged treatment; decreasing dosage or withdrawing drug for several days under medical supervision may restore responsiveness.a
If the patient is placed on a ventilator or corticosteroid therapy is begun, reduce dosage or eliminate neostigmine, if possible.a
Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects
Always have atropine and medications to treat shock readily available in case of hypersensitivity reaction.b
Give IV atropine sulfate or glycopyrrolate immediately prior to or concurrently with neostigmine (in separate syringes) when reversing the actions of nondepolarizing neuromuscular blocking agents to minimize neostigmine's adverse muscarinic effects.103 a b If bradycardic, give IV antimuscarinics before neostigmine to increase pulse rate to about 80 bpm.a b
Optimum time for neostigmine administration is during hyperventilation when blood CO2 concentration is low.b
Patient must be well ventilated; maintain patent airway until complete recovery of normal respiration is assured.a b Observe closely for recurrent respiratory depression.a
Parenteral Administration
Administration
Administer neostigmine bromide orally; administer neostigmine methylsulfate IV, IM, or sub-Q.a b c
Oral Administration
Administer orally, adjusting frequency and timing of administration according to individual response.a
Parenteral Administration
For solution and drug compatibility information, see Compatibility under Stability.
Administer neostigmine methylsulfate IV, IM, or sub-Q.a b
Surgery: Give by slow IV injection.a
Dosage
Available as neostigmine bromide and neostigmine methylsulfate; dosage expressed in terms of the salts.a b c
Pediatric Patients
Myasthenia Gravis
Diagnosis
IM
Children: 0.025–0.04 mg/kg.103 a Give 0.011 mg/kg atropine sulfate sub-Q or IM 30 minutes before neostigmine or IV immediately before the IM neostigmine test dose.103 a (See Pediatric Use under Cautions.)
Treatment
Oral
2 mg/kg daily divided into doses administered every 3–4 hours as needed.103 (See Pediatric Use under Cautions.)
Adjust dosage so the patient takes larger doses at times of greatest fatigue (e.g., 30 minutes before meals if difficulty eating).a c
Oral dosage changes may take several days to show results.a When a further increase in dosage produces no corresponding increase in muscle strength, reduce dosage to the previous level.a
Oral dosage requirements are approximately 30 times parenteral dosage requirements.a Generally 15 mg oral neostigmine bromide is equivalent to 0.5 mg parenteral neostigmine methylsulfate.c
IM, IV, or Sub-Q
0.01–0.04 mg/kg every 2–4 hours.103 104 In neonates, myasthenia gravis tends to be self-limiting; gradually reduce daily dosage until drug can be withdrawn.a (See Pediatric Use under Cautions.)
Surgery
Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects
IV
Infants: 0.025–0.1 mg/kg (with atropine sulfate or glycopyrrolate).103 (See Pediatric Use under Cautions.)
Children: 0.025–0.08 mg/kg (with atropine sulfate or glycopyrrolate).103
Adults
Myasthenia Gravis
Diagnosis
IM
0.022 mg/kg.103 a Give 0.011 mg/kg atropine sulfate IM 30 minutes before the test or IV atropine sulfate immediately before the IM neostigmine test dose.a
If cholinergic reaction occurs, discontinue test and give 0.4–0.6 mg or more IV atropine sulfate.a
If test is inconclusive, retest another day using 0.031 mg/kg neostigmine methylsulfate IM preceded by 0.016 mg/kg IM atropine sulfate.a
Treatment
Oral
Initially, 15 mg 3 times daily.a Increase gradually at intervals ≥24 hours.a
Usual maintenance dosage: 15–375 mg daily (average 150 mg daily);a c some patients may require 30–40 mg every 2–4 hours.a
Adjust dosage so the patient takes larger doses at times of greatest fatigue (e.g., 30 minutes before meals if difficulty eating).a c
Oral dosage changes may take several days to show results.a When a further increase in dosage produces no corresponding increase in muscle strength, reduce dosage to the previous level.a
Oral dosage requirements are approximately 30 times parenteral dosage requirements.a Generally 15 mg oral neostigmine bromide is equivalent to 0.5 mg parenteral neostigmine methylsulfate.c
IV, IM, or Sub-Q
Initially, 0.5–2.5 mg as needed.a
Give 0.6–1.2 mg IV atropine sulfate concurrently with (but in a separate syringe) large parenteral neostigmine doses to counteract adverse muscarinic effects; observe patient closely for cholinergic reactions.a b
Surgery
Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects
IV
0.5–2.5 mg.a Give concurrently with (but in a separate syringe) or immediately after 0.6–1.2 mg IV atropine sulfatea b or 0.2–0.6 mg glycopyrrolate.a Repeat as required; total neostigmine methylsulfate dose usually ≤5 mg.b
For cardiac or severely ill patients, titrate dosage with a peripheral nerve stimulator.a b
Full recovery usually occurs within 3–5 minutes but may be delayed in patients with extreme debilitation, hypokalemia, or carcinomatosis, or with concurrent use of certain broad spectrum antibiotics (e.g., aminoglycosides) or anesthetic agents (e.g., ether).a
Postoperative Distention and Urinary Retention
Prevention
IM or Sub-Q
0.25 mg as soon as possible after surgery; repeat every 4–6 hours for 2–3 days.a b
Treatment
IM or Sub-Q
0.5 mg; exclude mechanical obstruction before giving neostigmine.a b
If no response within 1 hour of first dose in patients with urinary retention, catheterize patient; repeat 0.5-mg doses every 3 hours for at least 5 doses after bladder is emptied.a b
Prescribing Limits
Adults
Surgery
Reversal of Nondepolarizing Neuromuscular Blocking Agent Effects
IV
Usually do not exceed total dose of 5 mg.a b
Special Populations
No special population dosage recommendations at this time.a b c
Cautions for Neostigmine Bromide
Contraindications
Known hypersensitivity to neostigmine.a b c
Mechanical obstruction of the intestinal or urinary tract.a b c
Peritonitis.a b c
Neostigmine bromide should not be used in patients with known hypersensitivity to bromides.a c
Warnings/Precautions
Warnings
Cholinergic Crisis
Overdosage may result in cholinergic crisis (e.g., excessive salivation and sweating, miosis, nausea, vomiting, diarrhea, bradycardia or tachycardia, hypotension, confusion, seizures, coma, severe muscle weakness, paralysis); may result in death.a b c If overdosage occurs, withdraw all anticholinesterase drugs, maintain adequate respiration, and give IV atropine.a b c
Myasthenic crisis due to increased disease severity also causes extreme muscle weakness; symptomatic differentiation from cholinergic crisis may be difficult.a b c Time to onset of symptoms approximately 1 hour after dose suggests neostigmine overdosage; onset 3 hours after dose suggests underdosage or resistance.a May require use of edrophonium chloride for the differential diagnosis.a b c
If severe cholinergic reaction occurs, discontinue immediately and institute appropriate therapy as indicated (e.g., atropine sulfate).a b c
Concomitant Diseases
Use with caution in patients with epilepsy, bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias, or peptic ulcer.b c
Avoid large oral doses in patients with megacolon or decreased GI motility because of risk of accumulation and toxicity when GI motility is restored.a Also avoid large oral doses in conditions that might cause increased absorption from the intestinal tract.c
Do not use in patients with peritonitis or doubtful bowel viability.a
Ileorectal Anastomoses
Neostigmine-induced peristalsis may disrupt recently completed ileorectal anastomoses if given postoperatively.a Halothane anesthesia may decrease risk; however, manufacturer states neostigmine should not be administered in the presence of high concentrations of halothane or cyclopropane.a b
Sensitivity Reactions
Bromide Sensitivity
Use caution in patients with known bromide sensitivity; acneiform rash may develop.a Usually disappears when neostigmine bromide is discontinued.a
Specific Populations
Pregnancy
Category C.b c
Risk of uterine irritability and induction of premature labor if anticholinesterase agents are given IV near term.b c
Lactation
Not known whether neostigmine is distributed into milk.b c Discontinue nursing or the drug.b c
Pediatric Use
Manufacturers state that safety and efficacy have not been established in pediatric patients, but the drug has been used in this population (e.g., neonatal myasthenia gravis).103 104 b c
Common Adverse Effects
Salivation, muscle fasciculation, intestinal cramps, diarrhea.a b c
Interactions for Neostigmine Bromide
Specific Drugs
Drug
|
Interaction
|
Comments
|
|---|
Aminoglycosides (e.g., kanamycin, neomycin, streptomycin )
|
Possible accentuation of neuromuscular blockadea b c
|
Use cautiously, if at all;a neostigmine dosage adjustment may be neededa b c
|
Anesthetics, local and general
|
Interferes with neuromuscular transmissiona b c
|
Use cautiously, if at all;a neostigmine dosage adjustment may be neededa b c
Do not administer neostigmine in presence of high halothane or cyclopropane concentrationsa b
|
Antiarrhythmic agents
|
Interferes with neuromuscular transmissiona b c
|
Use cautiously, if at all;a neostigmine dosage adjustment may be neededa b c
|
Anticholinergic drugs
|
Possible reduced intestinal motilityc
|
Use caution if co-administered with oral neostigminec
|
Atropine
|
Antagonizes muscarinic effects of neostigminea
|
Interaction used to therapeutic advantage to counteract muscarinic symptoms of neostigmine toxicity; however, atropine also may mask manifestations of neostigmine overdose and prevent early detection of cholinergic crisisa b c
|
Dexpanthenol
|
Converted to pantothenic acid in vivo; possible additive effects due to increased acetylcholine productiona
|
|
Neuromuscular blocking agents, depolarizing (e.g., decamethonium [no longer commercially available in the US], succinylcholine)
|
Possible enhanced and/or prolonged neuromuscular blockadea b c
|
Do not use for reversal of depolarizing neuromuscular blockadea
|
Neuromuscular blocking agents, nondepolarizing (e.g., gallamine, metocurine, tubocurarine [all no longer commercially available in the US], pancuronium)
|
Antagonism of nondepolarizing muscle relaxant effectsa
|
Interaction used to therapeutic advantage to reverse muscle relaxation induced by neuromuscular blocking agents after surgerya
|
Neostigmine Bromide Pharmacokinetics
Absorption
Bioavailability
Poorly absorbed (1–2%) from GI tract following oral administration.a c
Peak plasma concentrations occur 1–2 hours after oral ingestion with considerable interindividual variations or about 30 minutes after IM injection.a b c
Onset
Effects on peristaltic activity begin 2–4 hours after oral administration or 10–30 minutes after parenteral injection.a b
Maximal effects within 20–30 minutes after parenteral administration.a
Duration
2.5–4 hours after IM injection.a b
Distribution
Extent
Not expected to cross the placenta in therapeutic doses; may cross the placenta with large oral doses.a Not known whether distributed into human milk.a
Plasma Protein Binding
15–25% to serum albumin.a b c
Elimination
Metabolism
Metabolized via hydrolysis by cholinesterases and by microsomal enzymes in the liver.a b c
Elimination Route
Excreted in urine as unchanged drug (50%) and metabolites (30%).a b
Half-life
Oral: 42–60 minutes (mean: 52 minutes).c
IV: 47–60 minutes (mean: 53 minutes).b
IM: 51–90 minutes.b
Stability
Storage
Oral
Tablets
Tight containers at <40°C; preferably 15–30°C.a
Parenteral
Injection
15–30°C.b Protect from light; store in carton until use.b Do not freeze.a
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Drug Compatibility
Y-Site Compatibility (Neostigmine Methylsulfate)HID
Compatible
|
Heparin sodium
|
Hydrocortisone sodium succinate
|
Potassium chloride
|
Vitamin B complex with C
|
Compatibility in Syringe (Neostigmine Methylsulfate)HID
Compatible
|
Glycopyrrolate
|
Heparin sodium
|
Ondansetron HCl
|
Pentobarbital sodium
|
Thiopental sodium
|
ActionsActions
Reversibly inhibits acetylcholinesterase and prolongs and exaggerates the effects of acetylcholine.a b c Has direct cholinomimetic effect on skeletal muscle.a b c
Produces generalized cholinergic responses including miosis, bradycardia, increased tonus of intestinal musculature, constriction of bronchi and ureters, and stimulation of secretion by salivary and sweat glands.a
At sufficiently high dosage, directly blocks action at autonomic ganglia, causes CNS stimulation followed by CNS depression and, ultimately, depolarization blockade.a c
Advice to Patients
Patients with myasthenia gravis: Importance of carefully following prescribed dosage instructions.a Importance of keeping a daily record of condition to assist clinician in determining optimal therapeutic regimen.c
Importance of informing clinician of any allergy to bromide or anticholinesterase drugs.a c
Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.a b c
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a b c
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Neostigmine Bromide
Routes
|
Dosage Forms
|
Strengths
|
Brand Names
|
Manufacturer
|
|---|
Bulk
|
Powder
|
|
|
|
Oral
|
Tablets
|
15 mg
|
Prostigmin (scored)
|
Valeant
|
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Neostigmine Methylsulfate
Routes
|
Dosage Forms
|
Strengths
|
Brand Names
|
Manufacturer
|
|---|
Bulk
|
Powder*
|
|
|
|
Parenteral
|
Injection
|
0.5 mg/mL*
|
Neostigmine Methylsulfate Injection
|
Abraxis, American Regent, Baxter, Teva
|
|
|
1 mg/mL*
|
Neostigmine Methylsulfate Injection
|
Abraxis, American Regent, Baxter, Teva
|
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions February 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
100. Miller LS, Staas WE Jr, Herbison GJ. Abdominal problems in patients with spinal cord lesions. Arch Phys Med Rehabil. 1975; 56:405-8. [PubMed 1164181]
101. Glick ME, Meshkinpour H, Haldeman S et al. Colonic dysfunction in patients with thoracic spinal cord injury. Gastroenterology. 1984; 86:287-94. [PubMed 6690355]
102. Miller LS. Neostigmine for severe constipation with spinal cord lesions. Ann Intern Med. 1984; 101:279.
103. Gunn VL, Nechyba C, eds. The Harriet Lane handbook: a manual for pediatric house officers. 16th ed. Philadelphia, PA: Mosby; 2002:772
104. Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:2470
a. AHFS drug information 2007. McEvoy GK, ed. Neostigmine bromide, neostigmine methylsulfate. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1245-7.
b. American Regent Laboratories, Inc. Neostigmine methylsulfate injection, USP prescribing information. Shirley, NY; 2002 Sept.
c. ICN Pharmaceuticals, Inc. Prostigmin (neostigmine bromide) tablets prescribing information. Costa Mesa, CA; 1998 Nov.
HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:1203-4.
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