Neostigmine Methylsulfate

Class: Parasympathomimetic (Cholinergic) Agents
Note: This monograph also contains information on Neostigmine Bromide
VA Class: AU300
CAS Number: 59-99-4
Brands: Prostigmin

Introduction

Reversible anticholinesterase agent.^{a b c}

Uses for Neostigmine Methylsulfate

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 Methylsulfate 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 impractical^b 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

• 
  

  Prior or simultaneous administration of atropine may be advisable when administering large parenteral doses of neostigmine methylsulfate.^{a b}

  
  

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 sulfate^{a 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 Methylsulfate

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 Methylsulfate

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 Methylsulfate 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.

More Neostigmine Methylsulfate resources

• Neostigmine Methylsulfate Side Effects (in more detail)
• Neostigmine Methylsulfate Use in Pregnancy & Breastfeeding
• Neostigmine Methylsulfate Drug Interactions
• Neostigmine Methylsulfate Support Group
• 0 Reviews for Neostigmine Methylsulfate - Add your own review/rating

Compare Neostigmine Methylsulfate with other medications

• Myasthenia Gravis