Version October 2023
Myasthenia gravis, treatment: Canadian labeling:
Oral: Initial: 15 mg administered 3 times daily. Usual daily dose: 150 mg/day in divided doses; interval between doses should be adjusted per patient response with larger doses provided at times of most fatigue. Usual daily dosage range: 15 to 375 mg/day.
Reversal of nondepolarizing neuromuscular blockade after surgery:
Note : An anticholinergic agent (atropine or glycopyrrolate) should be given intravenously prior to (if patient is bradycardic) or in conjunction with neostigmine (to prevent bradycardia and GI symptoms). Avoid use or use with caution in patients with certain neuromuscular diseases (eg, myasthenia gravis, muscular dystrophy); other agents may be preferred (eg, sugammadex); if neostigmine is used, reduced dosing may be required with titration based on train-of-four (TOF) monitoring (Ref). TOF monitoring should be used to determine time of neostigmine initiation and need for additional doses. Dosing may vary depending on patient specific factors (eg, depth of paralysis, type of anesthesia, organ dysfunction, age, acid-base status) (Ref). Refer to institutional protocols and policies.
Usual dose: IV: 0.02 to 0.07 mg/kg; generally achieves a TOF twitch ratio of 90% within 10 to 20 minutes of administration; maximum total dose: 0.07 mg/kg or 5 mg (whichever is less) (Ref).
Dose selection based on TOF count at end of surgery (Ref):
TOF count 1 or no TOF response: Delay reversal until TOF count ≥2.
TOF count 2 or 3: 0.07 mg/kg; allow at least 15 to 30 minutes before tracheal extubation.
TOF count 4 with observable fade: 0.04 to 0.05 mg/kg; allow at least 10 to 15 minutes before tracheal extubation.
TOF count 4 with no observable fade: 0.02 mg/kg.
Acute colonic pseudo-obstruction (Ogilvie syndrome) (off-label use): Note: Continuous cardiac monitoring with clinical assessment for 30 minutes after administration. Atropine should be available at the bedside if bradyarrhythmia occurs (Ref).
Bolus: IV: 2 mg over 3 to 5 minutes (Ref).
Intermittent infusion: IV: 2.5 mg over 60 minutes (Ref).
Continuous infusion: IV: 0.4 mg per hour for up to 8 hours; if no response increase to 0.8 mg per hour for up to 24 hours (Ref).
There are no dosage adjustments provided in manufacturer's labeling. The manufacturer recommends close monitoring in patients with impaired renal function.
The following adjustments have been recommended (Ref):
CrCl >50 mL/minute: No dosage adjustment necessary
CrCl 10 to 50 mL/minute: Administer 50% of normal dose.
CrCl <10 mL/minute: Administer 25% of normal dose.
Hemodialysis: No dosage adjustment necessary
Peritoneal dialysis: No dosage adjustment necessary
Continuous renal replacement therapy (CRRT): Administer 50% of normal dose
There are no dosage adjustments provided in manufacturer's labeling; has not been studied.
Refer to adult dosing.
(For additional information see "Neostigmine: Pediatric drug information")
Note: Neostigmine (Prostigmin) tablets have been discontinued in the US for more than 1 year.
Myasthenia gravis: Limited data available:
Diagnosis: Note: Pretreatment with atropine is recommended, and atropine should be available. IV fluids also recommended. Children <2 years: IM: 0.04 mg/kg once; if results equivocal or negative, may be repeated once in 4 hours. Typical dose is 0.5 to 1.5 mg (Ref)
Treatment: Note: Dosage requirements are variable; dosage should be individualized: Children and Adolescents:
Oral: 0.3 to 2 mg/kg/day in divided doses (Ref)
IM, IV, SubQ: 0.01 to 0.04 mg/kg every 2 to 6 hours (Ref)
Reversal of nondepolarizing neuromuscular blockade after surgery: Infants, Children, and Adolescents: IV:
Manufacturer labeling: Bloxiverz: Note: An anticholinergic agent (atropine or glycopyrrolate) should be given prior to or in conjunction with neostigmine; in the presence of bradycardia, administer the anticholinergic prior to neostigmine. Peripheral nerve stimulation delivering train-of-four (TOF) stimulus must also be used to determine time of neostigmine initiation and need for additional doses.
Usual dose: 0.03 to 0.07 mg/kg generally achieves a TOF twitch ratio of 90% within 10 to 20 minutes of administration; maximum total dose: 0.07 mg/kg or 5 mg (whichever is less)
Dose selection guide:
The 0.03 mg/kg dose is recommended for reversal of NMBAs with shorter half-lives (eg, rocuronium); or when the first twitch response to the TOF stimulus is substantially >10% of baseline or when a second twitch is present.
The 0.07 mg/kg dose is recommended for NMBAs with longer half-lives (eg, vecuronium, pancuronium); or when the first twitch response is relatively weak (ie, not substantially >10% of baseline); or rapid recovery is needed.
Alternate dosing: Generic injectable products: Limited data available (Ref): Infants and Children: 0.025 to 0.1 mg/kg/dose
There are no dosage adjustments provided in manufacturer's labeling; however, based on experience in adult patients, dosing adjustment suggested.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.
1% to 10%:
Cardiovascular: Atrioventricular block, cardiac arrhythmia (including atrioventricular nodal arrhythmia, bradycardia [Ruetzler 2022], tachycardia), flushing, hypotension, syncope
Dermatologic: Diaphoresis, pruritus, skin rash, urticaria
Gastrointestinal: Flatulence, increased peristalsis, nausea, sialorrhea, vomiting, xerostomia
Genitourinary: Urinary frequency
Hematologic & oncologic: Oxygen desaturation
Hypersensitivity: Anaphylaxis (Ruetzler 2022), hypersensitivity reaction
Nervous system: Asthenia, dizziness, drowsiness, dysarthria, headache, insomnia, loss of consciousness, postanesthetic shivering, seizure
Neuromuscular & skeletal: Arthralgia, muscle cramps, muscle spasm
Ophthalmic: Miosis, visual disturbance
Respiratory: Apnea, bronchospasm (Ruetzler 2022), dyspnea, increased bronchial secretions (including pharyngeal secretions), respiratory depression
Postmarketing:
Cardiovascular: ECG changes (nonspecific)
Gastrointestinal: Abdominal cramps, diarrhea
Neuromuscular & skeletal: Fasciculations
Hypersensitivity to neostigmine or any component of the formulation; peritonitis or mechanical obstruction of the intestinal or urinary tract.
Canadian labeling (tablets only): Additional contraindications (not in US labeling): Hypersensitivity to bromides.
Documentation of allergenic cross-reactivity for cholinesterase inhibitors is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Cardiovascular effects: Bradycardia, hypotension, and dysrhythmias may occur, particularly with IV use; risk may be increased in patients with certain cardiovascular conditions (eg, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome). Risk may also be increased in patients with myasthenia gravis. When IV neostigmine is administered for the reversal of nondepolarizing neuromuscular-blocking agents, atropine or glycopyrrolate should be administered concurrently or prior to neostigmine to lessen the risk of bradycardia.
• Cholinergic crisis: Overdosage may result in cholinergic crisis, characterized by extreme muscle weakness and potentially fatal respiratory paralysis. Cholinergic crisis should be distinguished from myasthenic crisis, which is also characterized by extreme muscle weakness, but would require radically different treatment.
• Hypersensitivity reactions: Symptoms of hypersensitivity have included anaphylaxis, angioedema, bradycardia, bronchospasm, erythema multiforme, facial swelling, flushing, generalized rash, hypotension, peripheral edema, pyrexia, and urticaria. Have atropine and epinephrine ready to treat hypersensitivity reactions.
• Neuromuscular effects: Large doses of IV neostigmine administered for the reversal of nondepolarizing neuromuscular-blocking agents when neuromuscular blockade is minimal can result in neuromuscular dysfunction. Reduce dose if recovery from neuromuscular blockade is nearly complete.
Disease-related concerns:
• Asthma: Use with caution in patients with asthma.
• Cardiovascular disease: Use with caution in patients with bradycardia, cardiac arrhythmias, coronary artery disease, or recent acute coronary syndrome.
• Hyperthyroidism: Use with caution in patients with hyperthyroidism.
• Megacolon/GI dysfunction: Large oral doses should be avoided with megacolon or decreased GI motility. Neostigmine may accumulate; toxicity may result when motility is restored.
• Neuromuscular diseases: For reversal of nondepolarizing neuromuscular blockade, avoid use or use with caution in patients with certain neuromuscular diseases (eg, myasthenia gravis, muscular dystrophy); other agents may be preferred (eg, sugammadex); if used, reduced dosing may be required with titration based on train-of-four monitoring (Balaka 2011; Briggs 2003; Buzello 1982). Adequate facilities should be available for cardiopulmonary resuscitation when testing and adjusting dose for myasthenia gravis.
• Peptic ulcer disease: Use with caution in patients with peptic ulcer disease.
• Seizure disorder: Use with caution in patients with epilepsy.
• Vagotonia: Use with caution in patients with vagotonia.
Special populations:
• Pediatric: When used IV for the reversal of nondepolarizing muscle relaxants, pediatric and adult dosing is similar. However, recovery may be more rapid and risk of complications may be greater in infants and small children. Monitor closely.
• Older adult: Use with caution and monitor for a longer period. Elderly patients experience slower spontaneous recovery from neuromuscular blocking agents.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous, as methylsulfate:
Bloxiverz: 5 mg/10 mL (10 mL); 10 mg/10 mL (10 mL) [contains phenol]
Generic: 5 mg/10 mL (10 mL); 10 mg/10 mL (10 mL)
Solution Prefilled Syringe, Intravenous, as methylsulfate:
Generic: 3 mg/3 mL (3 mL)
Yes
Solution (Bloxiverz Intravenous)
5 mg/10 mL (per mL): $2.08
10 mg/10 mL (per mL): $2.20
Solution (Neostigmine Methylsulfate Intravenous)
5 mg/10 mL (per mL): $0.72 - $3.24
10 mg/10 mL (per mL): $0.72 - $3.36
Solution Prefilled Syringe (Neostigmine Methylsulfate Intravenous)
3 mg/3 mL (per mL): $6.00
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Injection:
Generic: 2.5 mg/mL (5 mL)
Solution, Injection, as methylsulfate:
Generic: 0.5 mg/mL (1 mL, 10 mL); 1 mg/mL (1 mL, 10 mL)
Tablet, Oral, as bromide:
Prostigmin: 15 mg [DSC]
Tablets (neostigmine bromide): Prostigmin [Canadian product]: Muscarinic effects may be decreased when administered with food or milk. Consider giving larger portions of the daily dose around fatigue prone times (eg, mealtimes, afternoons).
Injectable (neostigmine methylsulfate):
Neostigmine Omega, Prostigmin [Canadian products]: May be administered IM, IV, or SUBQ.
Bloxiverz: Administer by slow IV injection over at least 1 minute.
Acute colonic pseudo-obstruction (off-label use):
Bolus: IV: Administer over 3 to 5 minutes (Ref).
Intermittent infusion: IV: Administration over 60 minutes (Ref).
Continuous infusion: IV: Refer to indication-specific infusion rates in "Dosing: Adult" for detailed recommendations (Ref).
Parenteral: May be administered undiluted by slow IV injection over several minutes; may be administered IM or SubQ
Oral: Divide dosages so patient receives larger doses at times of greatest fatigue; may be administered with or without food
US labeling:
Reversal of nondepolarizing muscle relaxants: Reversal of effects of nondepolarizing neuromuscular blocking agents after surgery.
Canadian labeling:
Myasthenia gravis: Symptomatic control of myasthenia gravis (oral product).
Limitations of use: Other agents may be preferred for symptomatic treatment or acute exacerbations.
Acute colonic pseudo-obstruction (Ogilvie’s syndrome)
Bloxiverz may be confused with Vazculep (phenylephrine injection) due to similar packaging
Prostigmin may be confused with physostigmine
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Amifampridine: Acetylcholinesterase Inhibitors may enhance the therapeutic effect of Amifampridine. Amifampridine side effects may also be increased. Amifampridine may enhance the therapeutic effect of Acetylcholinesterase Inhibitors. Acetylcholinesterase inhibitor side effects may also be increased. Risk C: Monitor therapy
Anticholinergic Agents: Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Benoxinate: Acetylcholinesterase Inhibitors may enhance the therapeutic effect of Benoxinate. Specifically, the effects of benoxinate may be prolonged. Risk C: Monitor therapy
Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Risk C: Monitor therapy
Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Risk C: Monitor therapy
Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Risk D: Consider therapy modification
Chlorprothixene: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Chlorprothixene. Acetylcholinesterase Inhibitors may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Specifically, cholinergic effects may be enhanced or increased. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Risk C: Monitor therapy
Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy
Fexinidazole: Bradycardia-Causing Agents may enhance the arrhythmogenic effect of Fexinidazole. Risk X: Avoid combination
Fingolimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Fingolimod. Management: Consult with the prescriber of any bradycardia-causing agent to see if the agent could be switched to an agent that does not cause bradycardia prior to initiating fingolimod. If combined, perform continuous ECG monitoring after the first fingolimod dose. Risk D: Consider therapy modification
Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Risk C: Monitor therapy
Kanamycin: Neostigmine may diminish the therapeutic effect of Kanamycin. Risk C: Monitor therapy
Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Risk C: Monitor therapy
Midodrine: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: Monitor therapy
Ozanimod: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Ponesimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Ponesimod. Management: Avoid coadministration of ponesimod with drugs that may cause bradycardia when possible. If combined, monitor heart rate closely and consider obtaining a cardiology consult. Do not initiate ponesimod in patients on beta-blockers if HR is less than 55 bpm. Risk D: Consider therapy modification
Siponimod: Bradycardia-Causing Agents may enhance the bradycardic effect of Siponimod. Management: Avoid coadministration of siponimod with drugs that may cause bradycardia. If combined, consider obtaining a cardiology consult regarding patient monitoring. Risk D: Consider therapy modification
Succinylcholine: Acetylcholinesterase Inhibitors may enhance the neuromuscular-blocking effect of Succinylcholine. Risk C: Monitor therapy
Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Risk C: Monitor therapy
Adverse events were not observed in animal reproduction studies (doses used were below maximum expected human exposure based on BSA).
Anticholinesterases have caused uterine irritability and induced premature labor with IV use in pregnant patients near term. When used as adjunct to analgesia in labor, adverse events to the fetus and mother are dose- and route-dependent (Habib 2006). Neostigmine may be used to treat myasthenia gravis in pregnant patients; however, if an acetylcholinesterase inhibitor is needed during pregnancy, another agent may be preferred (Bansal 2018; Hassan 2017; Norwood 2014; Sanders 2016).
It is not known if neostigmine is present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Babies born to mothers with myasthenia gravis may have feeding difficulties due to transient myasthenia gravis of the newborn (Norwood 2014).
ECG, blood pressure, and heart rate especially with IV use; train-of-four monitoring; consult individual institutional policies and procedures.
Acute colonic pseudo-obstruction (off-label use): Keep patient supine upon administration. Patient should receive continuous ECG monitoring with clinical assessment for 30 minutes after administration (Saunders 2005).
Inhibits destruction of acetylcholine by acetylcholinesterase which facilitates transmission of impulses across myoneural junction; direct cholinomimetic effect on skeletal muscle and possible on autonomic ganglion cells and neurons of the CNS
Onset of action: Peristaltic activity: Oral: 2 to 4 hours; Parenteral: 10 to 30 minutes
Duration: IM: 2.5 to 4 hours
Absorption: Oral: Poor (~1% to 2%)
Distribution: Vd: IV: 0.12 to 1.4 L/kg
Protein binding: 15% to 25% to albumin
Metabolism: Hepatic
Half-life elimination:
IM: Adults: 51 to 90 minutes
IV: Range: 24 to 113 minutes
Infants 2 to 10 months: Mean: 39 ± 5 minutes
Children 1 to 6 years: Mean: 48 ± 16 minutes
Adults 29 to 48 years: 67 ± 8 minutes
Anephric patients: 181 ± 54 minutes
Renal transplant recipients: 104.7 ± 64 minutes
Oral: Adults: 42 to 60 minutes
Time to peak: Oral: 1 to 2 hours (Aquilonius 1986)
Excretion: Urine (50% as unchanged drug; remainder as metabolites) (Aquilonius 1986)
Altered kidney function: Elimination half-life prolonged in anephric patients.
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