Class: Parasympathomimetic (Cholinergic) Agents
- Anticholinesterase Agents
VA Class: AU300
CAS Number: 59-99-4
Brands: Bloxiverz

Medically reviewed by Drugs.com. Last updated on May 18, 2020.

• Overview
• Side Effects
• Dosage
• Professional
• Interactions
• More

Introduction

Anticholinesterase agent.^{105 109 120 130}

Uses for Neostigmine

Reversal of Neuromuscular Blockade

Reversal of the effects of nondepolarizing neuromuscular blocking agents (e.g., atracurium, cisatracurium, 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}

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, oral preparation (e.g., Prostigmin) previously used for this indication no longer commercially available in the US.^{106 107 108 109 110 111 131}

If an anticholinesterase agent is required for symptomatic treatment of myasthenia gravis, pyridostigmine is the preferred drug.^{107 109 132}

Also has been used for diagnostic testing of myasthenia gravis†.^{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 Dosage and Administration

General

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

Administration

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}

Dosage

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

Pediatric Patients

Reversal of Neuromuscular Blockade

IV

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†

Diagnosis

IM

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

Treatment

IM, IV, or Sub-Q

If parenteral therapy required in patients with myasthenia gravis, 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

Adults

Reversal of Neuromuscular Blockade

IV

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†

Diagnosis

IM

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

Treatment

IV, IM, or Sub-Q

If parenteral therapy required in patients with myasthenia gravis, 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

IV

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

Adults

Reversal of Neuromuscular Blockade

IV

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

Contraindications

• Known hypersensitivity to neostigmine.¹⁰⁵

• Mechanical obstruction of the intestinal or urinary tract.¹⁰⁵

• Peritonitis.¹⁰⁵

Warnings/Precautions

Warnings

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

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

Pregnancy

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

Lactation

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

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

Neostigmine Pharmacokinetics

Absorption

Bioavailability

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

Onset

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

Duration

2.5–4 hours after IM injection.^a

Distribution

Extent

Not known whether distributed into human milk.¹⁰⁵

Plasma Protein Binding

15–25% to serum albumin.¹⁰⁵

Elimination

Metabolism

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

Half-life

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

Stability

Storage

Parenteral

Injection

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

Compatibility

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

Drug Compatibility

Actions

• 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.)

Preparations

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

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