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Neostigmine Methylsulfate


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


Anticholinesterase agent.105 109 120 130

Uses for Neostigmine Methylsulfate

Reversal of Neuromuscular Blockade

Postoperative reversal of the effects of nondepolarizing neuromuscular blocking agents (e.g., atracurium, cisatracurium, mivacurium, pancuronium, rocuronium, vecuronium).23 24 39 105 119 126 Use in conjunction with an anticholinergic agent (atropine sulfate or glycopyrrolate) to counteract adverse muscarinic effects (e.g., bradycardia, bradyarrhythmias, increased secretions, bronchoconstriction).105 120 121

Reduces time to recovery of neuromuscular function (defined as a return of train-of-four [TOF] twitch ratio to 0.9).105 119 123 126

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Not effective in antagonizing deep levels of neuromuscular blockade; attempt reversal only after some degree of spontaneous recovery has occurred (e.g., when there is a detectable twitch response to the first TOF stimulus).105 119 121 122 129

Do not use in patients with complete neuromuscular recovery; paradoxical neuromuscular effects (e.g., weakness of upper airway muscles, increased airway collapsibility) may occur.122 125 127 128 129 (See Neuromuscular Dysfunction under Cautions.)

Not effective and should not be used for reversal of depolarizing neuromuscular agents (e.g., succinylcholine).a

Myasthenia Gravis

Has been used for symptomatic treatment of myasthenia gravis to improve muscle strength; however, pyridostigmine generally preferred because of its longer duration of action and lower incidence of adverse muscarinic effects.106 107 108 109 110 111 131

An oral preparation (neostigmine bromide; Prostigmin) previously used for this indication no longer is commercially available in the US.

Also has been used for diagnostic testing of myasthenia gravis, although edrophonium usually preferred.106 107 109

GI Disorders

Has been used for treatment of acute colonic pseudo-obstruction or Ogilvie syndrome.112 113 114 May be effective as second-line therapy in patients who fail conservative therapy.112 113 114

Has been used as a prokinetic agent in patients with postoperative ileus following surgery; however, clinical usefulness may be limited by adverse muscarinic effects (e.g., bradycardia, increased bronchial secretions).115 116 117

Has been used in the management of severe constipation in patients with thoracic spinal cord injury.100 101 102

Neostigmine Methylsulfate Dosage and Administration


Reversal of Neuromuscular Blockade

  • Administer only by trained clinicians experienced in the use of neuromuscular blocking agents and their reversal agents.105

  • Always have atropine and medications to treat anaphylaxis (e.g., epinephrine) readily available in case of hypersensitivity reaction.103 105

  • Administer IV atropine sulfate or glycopyrrolate immediately prior to or concurrently (in separate syringes) with neostigmine to counteract adverse muscarinic effects.103 If bradycardic, give IV antimuscarinic before neostigmine.105

  • Patients must be well ventilated and have a patent airway prior to administration and until complete recovery of normal respiration.105

  • Use a peripheral nerve stimulator capable of delivering a TOF stimulus to determine when neostigmine should be administered and if additional doses are necessary.105

  • Attempt reversal with neostigmine only after some degree of spontaneous recovery has occurred (i.e., ≥10% recovery of the first twitch response).105

  • Continuously monitor patient until complete recovery of neuromuscular function is assured (based on TOF responses and ability to ventilate adequately and maintain a patent airway following tracheal extubation).105


Administer by IV injection.105 Also has been administered by IM or sub-Q injection.103 109 118 131 Has been administered orally (as neostigmine bromide);103 109 111 however, oral preparation no longer commercially available in the US.

Parenteral Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow IV injection over a period of at least 1 minute.105 118


Available as neostigmine methylsulfate; dosage expressed in terms of the salt.105

Pediatric Patients

Reversal of Neuromuscular Blockade

Manufacturer states that pediatric patients may receive the same doses recommended for adults.105 (See Adults under Dosage and Administration.)

Other experts have recommended IV doses of 0.025–0.1 mg/kg in infants and 0.025–0.08 mg/kg in children.103

Myasthenia Gravis

Single dose of 0.025–0.04 mg/kg has been recommended.

IM, IV, or Sub-Q

Some experts recommend 0.01–0.04 mg/kg every 2–4 hours as needed.103 104 In neonates, myasthenia gravis tends to be self-limiting.a


Reversal of Neuromuscular Blockade

Manufacturer states that a dose of 0.03–0.07 mg/kg usually is sufficient to achieve adequate recovery of neuromuscular function (i.e., TOF ratio 0.9) within 10–20 minutes.105 119

Individualize selection of dose based on half-life of neuromuscular blocking agent administered, degree of spontaneous recovery, and need for rapid reversal.105

To reverse neuromuscular blocking agents with shorter half-lives (e.g., rocuronium) or shallower blocks (i.e., first twitch response substantially >10% of baseline or when a second twitch is present): 0.03 mg/kg recommended.105

To reverse longer-acting neuromuscular blocking agents (e.g., pancuronium, vecuronium) or deeper blocks (i.e., first twitch response not substantially >10% of baseline), or when more rapid recovery is needed: 0.07 mg/kg recommended.105

Determine need for additional doses based on TOF monitoring.105

Myasthenia Gravis

Single dose of 0.02 mg/kg has been recommended.103

IV, IM, or Sub-Q

Some experts recommend 0.5–2.5 mg every 1–3 hours as needed up to a maximum of 10 mg per 24 hours.103

Prescribing Limits

Pediatric Patients

Reversal of Neuromuscular Blockade

Maximum total dose of 0.07 mg/kg or 5 mg, whichever is less.105 Higher doses unlikely to provide additional clinical benefit.125


Reversal of Neuromuscular Blockade

Maximum total dose of 0.07 mg/kg or 5 mg, whichever is less.105 Higher doses unlikely to provide additional clinical benefit.125

Special Populations

Hepatic Impairment

Dosage adjustment not necessary.105 (See Hepatic Impairment under Cautions.)

Renal Impairment

Dosage adjustment not necessary.105 (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment not required.105 (See Geriatric Use under Cautions.)

Cautions for Neostigmine Methylsulfate


  • Known hypersensitivity to neostigmine.105

  • Mechanical obstruction of the intestinal or urinary tract.105

  • Peritonitis.105



Cardiovascular Effects

Risk of adverse cardiovascular effects such as bradycardia, hypotension, tachycardia, and cardiac arrhythmias.105 107 120 121 Use with caution in patients with coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome, or myasthenia gravis; risk of cardiovascular complications may be increased in such patients.105

Administer an anticholinergic agent prior to or concomitantly with neostigmine to minimize risk.105

Neuromuscular Dysfunction

Paradoxical neuromuscular effects (e.g., weakness of upper airway muscles and increased airway collapsibility) can occur if neostigmine is administered to patients with complete or near complete neuromuscular recovery.105 122 125 127 129 Reduce dose if neuromuscular recovery is almost complete.105

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.105 a If overdosage occurs, withdraw all anticholinesterase drugs, maintain adequate respiration, and give IV atropine.105

Myasthenic crisis, a complication of myasthenia gravis, can also cause extreme muscle weakness.105 It is extremely important to differentiate between the conditions since treatment methods differ considerably.105 Whereas more intensive anticholinesterase therapy is required in myasthenic crisis, higher doses of neostigmine can have serious consequences in cholinergic crisis.105

Sensitivity Reactions


Hypersensitivity reactions, including urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia, and anaphylaxis, reported.105

Atropine and other drugs for treatment of anaphylaxis should be readily available.105

Specific Populations


Category C.105

Not known whether neostigmine can cause fetal harm when administered to pregnant women; use during pregnancy only if clearly indicated.105

May induce premature labor if given IV to pregnant women near term.105


Not known whether neostigmine is distributed into milk.105 Caution advised.105

Pediatric Use

May be used in pediatric patients of all ages to reverse the effects of nondepolarizing neuromuscular blocking agents.105 119 130

Although some pharmacokinetic parameters may differ in children compared with adults,130 manufacturer recommends same dosing guideline as in adults.105 (See Dosage under Dosage and Administration.)

Smaller doses usually required to reverse neuromuscular blockade in infants and children compared with adults;105 130 however, pediatric patients have a greater risk of incomplete reversal of neuromuscular blockade due to decreased respiratory reserve.105 Risk of administering higher doses of neostigmine (up to maximum recommended dosage) should not outweigh risk associated with incomplete reversal.105

Geriatric Use

Use with caution and increased monitoring.105 Duration of action of neostigmine is prolonged in geriatric patients; however, such patients also experience slower spontaneous recovery from neuromuscular blocking agents.105 Monitor for longer periods to ensure that additional doses of neostigmine are not necessary to adequately reverse neuromuscular blockade.105 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Carefully monitor if neuromuscular blocking agents with hepatic elimination or active metabolites are administered to patients with hepatic impairment; duration of the neuromuscular blocking agent may be prolonged and persist beyond the effects of neostigmine.105 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Closely monitor patients with renal impairment if a renally eliminated neuromuscular blocking agent is administered; effects of the neuromuscular blocking agent may persist beyond those of neostigmine.105 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Most adverse effects generally due to exaggerated pharmacologic effects, particularly at muscarinic receptors; such effects include nausea, vomiting, diarrhea, miosis, excessive salivation and sweating, increased bronchial secretions, abdominal cramps, and bronchoconstriction.105 107 120 121

Manufacturer states most common adverse effects are bradycardia, nausea, and vomiting.105

Interactions for Neostigmine Methylsulfate

Drug interaction studies not conducted to date.105 Clinically important drug interactions not likely to occur if neuromuscular monitoring is employed and both relaxants and reversal agents are titrated to effect.120

Drugs Affecting Hepatic Microsomal Enzymes

Metabolized by hepatic microsomal enzymes; caution advised when used concomitantly with drugs that inhibit or induce these enzymes.105

Specific Drugs




Anticholinergic agents (atropine, glycopyrrolate)

Antagonizes muscarinic effects of neostigmine105

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 crisis105

Neuromuscular blocking agents, depolarizing (e.g., succinylcholine)

Possible enhanced and/or prolonged neuromuscular blockadea

Do not use for reversal of depolarizing neuromuscular blocking agentsa

Neuromuscular blocking agents, nondepolarizing (e.g., atracurium, cisatracurium, pancuronium, rocuronium, vecuronium)

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



Poorly absorbed (1–2%) from GI tract following oral administration (oral preparation no longer commercially available in US).a

Peak plasma concentrations occur 1–2 hours after oral ingestion with considerable interindividual variations or about 30 minutes after IM injection.a


Effects on peristaltic activity begin 2–4 hours after oral administration or 10–30 minutes after parenteral injection.a

Maximal effects within 20–30 minutes after parenteral administration.a


2.5–4 hours after IM injection.a



Not known whether distributed into human milk.105

Plasma Protein Binding

15–25% to serum albumin.105



Metabolized via hydrolysis by cholinesterases and by microsomal enzymes in the liver.105 a

Elimination Route

Excreted in urine as unchanged drug (50%) and metabolites.a


IV: 24–113 minutes.105

IM: 51–90 minutes.a

Special Populations

Renal impairment reduces neostigmine clearance.119 Elimination half-life is prolonged in anephric individuals.105 119

Elimination half-life approximately 39, 48, or 67 minutes in infants 2–10 months of age, children 1–6 years of age, or adults 29–48 years of age, respectively.105





20–25°C (may be exposed to 15–30°).105 Protect from light and store in original carton until use.105


For information on systemic interactions resulting from concomitant use, see Interactions.

Drug Compatibility

Y-Site Compatibility (Neostigmine Methylsulfate)118


Heparin sodium

Hydrocortisone sodium succinate

Palonosetron HCl

Potassium chloride

Compatibility in Syringe (Neostigmine Methylsulfate)118



Heparin sodium

Ondansetron HCl

Pentobarbital sodium


  • Competitively inhibits acetylcholinesterase, reducing degradation of acetylcholine; as a result, acetylcholine accumulates at cholinergic synapses producing prolonged and exaggerated effects.105 109 120 130 a Has direct cholinomimetic effect on skeletal muscle.a

  • Increased acetylcholine at neuromuscular junction competes with and reverses the effects of nondepolarizing neuromuscular blocking agents.105 121

  • In patients with myasthenia gravis, enhances neuromuscular transmission, providing symptomatic improvement.106 107 109

  • Produces generalized cholinergic effects including miosis, bradycardia, increased tonus of intestinal musculature, constriction of bronchi and ureters, and stimulation of secretion by salivary and sweat glands.a

  • Because of its quaternary ammonium structure, does not readily cross blood-brain barrier at moderate doses; however, at high doses, CNS effects can occur.a

Advice to Patients

  • 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.105

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.105

  • Importance of informing patients of other important precautionary information. (See Cautions.)


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Neostigmine Methylsulfate


Dosage Forms


Brand Names




0.5 mg/mL*



Neostigmine Methylsulfate Injection

1 mg/mL*



Neostigmine Methylsulfate Injection

AHFS DI Essentials. © Copyright, 2004-2015, Selected Revisions September 29, 2015. 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.


Only references cited for selected revisions after 1984 are available electronically.

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a. AHFS drug information 2016. McEvoy GK, ed. Neostigmine methylsulfate. Bethesda, MD: American Society of Health-System Pharmacists; 2016.

HID. Trissel LA. Handbook on injectable drugs. 17th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2013:847.