Brand name: Bloxiverz
Drug class: Parasympathomimetic (Cholinergic) Agents
- Anticholinesterase Agents
VA class: AU300
CAS number: 59-99-4

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

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 39 105 119 126 139}

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

Appropriate reversal of neuromuscular blocking agents is critical for preventing postoperative residual neuromuscular blockade.^{120 121 122 123 150 151} Reversal of neuromuscular blockade should routinely be considered unless there is quantitative evidence indicating that no reversal is needed (TOF >0.9).^{122 139 154}

Myasthenia Gravis

Has been used for symptomatic treatment of myasthenia gravis^{† [off-label]} to improve muscle strength; however, oral preparation (e.g., Prostigmin) previously used for this indication no longer commercially available in the US.^{106 107 108 109 110 138}

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

GI Disorders

Has been used for treatment of acute colonic pseudo-obstruction or Ogilvie syndrome^{† [off-label]}.^{112 113 114 133} May be effective as second-line therapy in patients who fail conservative therapy.^{112 113 114 133}

Has been used as a prokinetic agent in patients with postoperative ileus following surgery^{† [off-label]}; 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^{† [off-label]}.^{100 101 102}

Neostigmine Dosage and Administration

General

Patient Monitoring

• When used for reversal of neuromuscular blockade, patients must be well ventilated and have a patent airway prior to administration and until complete recovery of normal respiration.¹⁰⁵ Continuous monitoring of neuromuscular function is recommended to ensure adequate reversal from the neuromuscular block.¹⁰⁵ To exclude with certainty the possibility of residual paralysis, use an objective (quantitative) method of monitoring such as peripheral nerve stimulation in conjunction with other clinical assessments (e.g., observation of skeletal muscle tone, respiratory measurements).^{105 120 122 123 124 127 130} Adequate recovery of neuromuscular function generally is defined as a train-of-four (TOF) ratio of 0.9 in addition to the patient's ability to maintain satisfactory ventilation and a patent airway.^{105 120} Recovery times may vary based on the patient's medical condition and duration of action of the specific neuromuscular blocking agent used.^{105 119}

Dispensing and Administration Precautions

• 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}

Other General Considerations

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

Administration

Administer by slow IV injection over a period of at least 1 minute.^{105 118} Also has been administered by IM or sub-Q injection.^{103 109 118 131 † [off-label]}

Parenteral Administration

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

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 to 0.07 mg/kg in neonates, 0.025–0.1 mg/kg in infants, and 0.025–0.08 mg/kg in children.¹⁰³

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 of 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 and extent of recovery of neuromuscular function.¹⁰⁵

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

Bradycardia

Bradycardia may occur.¹⁰⁵ Administer atropine or glycopyrrolate prior to neostigmine to lessen risk.¹⁰⁵

Serious Reactions with Coexisting Conditions

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 (e.g., atropine) 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 administer IV atropine.¹⁰⁵

Myasthenic crisis, a complication of myasthenia gravis, can also cause extreme muscle weakness.^{105 141} 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

Not known whether neostigmine can cause fetal harm when administered to pregnant women or can affect reproductive capacity; 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

Bradycardia, nausea, vomiting.¹⁰⁵

Drug Interactions

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

Distribution

Extent

Not known whether distributed into human milk.¹⁰⁵

Plasma Protein Binding

15–25% to serum albumin.¹⁰⁵

Elimination

Metabolism

Metabolized by microsomal enzymes in the liver.^{105 121}

Elimination Route

Excreted in urine as unchanged drug (50%).¹²¹

Half-life

IV: 24–113 minutes.¹⁰⁵

Special Populations

Hepatic impairment: Pharmacokinetics not studied.¹⁰⁵

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

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} 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

• Does not readily cross blood-brain barrier.¹⁰⁵

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.¹⁰⁵ (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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