Medically reviewed on August 12, 2018
(nee oh STIG meen)
- Neostigmine Bromide
- Neostigmine Methylsulfate
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Solution, Injection, as methylsulfate:
Generic: 0.5 mg/mL (10 mL [DSC]); 1 mg/mL (10 mL [DSC])
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)
Brand Names: U.S.
- Acetylcholinesterase Inhibitor
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
Oral: Poor (~1% to 2%)
Distribution: Vd: IV: 0.12 to 1.4 L/kg
Urine (50% as unchanged drug; remainder as metabolites) (Aquilonius 1986)
Onset of Action
Peristaltic activity: Oral: 2 to 4 hours; Parenteral: 10 to 30 minutes
Time to Peak
Oral: 1 to 2 hours (Aquilonius 1986)
Duration of Action
IM: 2.5 to 4 hours
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 patients: 104.7 ± 64 minutes
Oral: Adults: 42 to 60 minutes
15% to 25% to albumin
Special Populations: Renal Function Impairment
Elimination half-life prolonged in anephric patients.
Use: Labeled Indications
Reversal of nondepolarizing muscle relaxants: Reversal of effects of nondepolarizing neuromuscular blocking agents after surgery.
Myasthenia gravis: Symptomatic control of myasthenia gravis
Limitations of use: Other agents may be preferred for symptomatic treatment or acute exacerbations.
Postoperative bladder distention, Urinary retention: Prevention and treatment of postoperative bladder distention and urinary retention after mechanical obstruction has been excluded.
Reversal of nondepolarizing muscle relaxants: Reversal of effects of nondepolarizing neuromuscular blocking agents after surgery.
Off Label Uses
Acute colonic pseudo-obstruction (Ogilvie’s syndrome)
Data from a randomized, double-blind, placebo-controlled trial and other prospective and retrospective studies in patients with acute colonic pseudo-obstruction supports the use of neostigmine to decompress the colon [Abeyta 2001], [Paran 2000], [Ponec 1999], [Trevisani 2000]. Additional trials may be necessary to further define the role of neostigmine in the treatment of this condition.
Hypersensitivity to neostigmine or any component of the formulation; peritonitis or mechanical obstruction of the intestinal or urinary tract
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to bromides (tablets only)
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.
Myasthenia gravis: Diagnosis: Canadian labeling: Note: Pretreatment with atropine is recommended, and atropine should be available if a cholinergic reaction occurs. IM: 0.022 mg/kg as a single dose. If test is inconclusive, retesting can be done on a different day with a single dose of 0.031 mg/kg.
Myasthenia gravis: Treatment: Canadian labeling:
Oral: Initial dose: 15 mg 3 times daily. Usual dose: 150 mg in divided doses, administered over a 24-hour period; interval between doses should be adjusted per patient response with larger doses provided at times of most fatigue. Dosage range: 15 to 375 mg daily in divided doses.
IM, IV, SubQ: 0.5 to 2.5 mg; dosing based on individual patient response
Reversal of nondepolarizing neuromuscular blockade after surgery:
Bloxiverz: IV: Note: An anticholinergic agent (atropine or glycopyrrolate) should be given intravenously 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. Prior to administration, there must be a twitch response to the first stimulus in the TOF of at least 10% of baseline.
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.
Canadian labeling: IV: 0.5 to 2.5 mg; repeat as required. Only in exceptional cases should the total dose exceed 5 mg. Note: Administer with atropine 0.6 to 1.2 mg intravenously in a separate syringe several minutes before neostigmine.
Postoperative bladder distention/urinary retention: IM, SubQ: Canadian labeling:
Prevention: 0.25 mg as soon as possible after operation; repeat every 4 to 6 hours for 2 to 3 days.
Treatment: 0.5 to 1 mg; if urination does not occur within an hour, patient should be catheterized. After the bladder has emptied or patient has voided, doses may be repeated every 3 hours for 5 doses.
Acute colonic pseudo-obstruction (Ogilvie syndrome) (off-label use): IV: 2 mg over 3 to 5 minutes (Ponec 1999). Note: Administration over 60 minutes may reduce the incidence of bradycardia; however, efficacy may be reduced (Abeyta 2001). Ensure atropine is available at the bedside to treat symptomatic neostigmine-induced bradycardia.
Refer to adult dosing.
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 (Kliegman 2011).
Treatment: Note: Dosage requirements are variable; dosage should be individualized: Children and Adolescents:
Oral: 0.3 to 2 mg/kg/day in divided doses (Silvestri 2012)
IM, IV, SubQ: 0.01 to 0.04 mg/kg every 2 to 6 hours (Kliegman 2007; Kliegman 2011)
Reversal of nondepolarizing neuromuscular-blocking agents (NMBAs) after surgery (Bloxiverz): Infants, Children, and Adolescents: IV: Refer to adult dosing.
Dosing: Renal Impairment
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 (Aronoff 2007): Adults:
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
Dosing: Hepatic Impairment
There are no dosage adjustments provided in manufacturer's labeling; has not been studied.
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]: 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): Administer IV over 3 to 5 minutes (Ponec 1999). Administration over 60 minutes may reduce the incidence of bradycardia; however, efficacy may be reduced (Abeyta 2001).
Bloxiverz: Store between 20°C and 25°C (68°F and 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light. Store in carton until time of use.
Neostigmine Omega [Canadian product]: Store at 15°C to 30°C; protect from light; multiple use vials should be discarded 28 days after initial use.
Prostigmin [Canadian product]: Store at 15°C to 30°C; protect from light.
Tablets: Prostigmin [Canadian product]: Store at 15°C to 30°C; protect from light.
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. Monitor therapy
Anticholinergic Agents: Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy
Benoxinate: Acetylcholinesterase Inhibitors may enhance the therapeutic effect of Benoxinate. Specifically, the effects of benoxinate may be prolonged. Monitor therapy
Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy
Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Monitor therapy
Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Monitor therapy
Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Monitor therapy
Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Monitor therapy
Succinylcholine: Acetylcholinesterase Inhibitors may increase the serum concentration of Succinylcholine. Management: Consider alternatives to this combination due to a risk of prolonged neuromuscular blockade. Consider therapy modification
Frequency not defined.
Cardiovascular: Atrioventricular block, cardiac arrhythmia (especially bradycardia), ECG changes (nonspecific), flushing, hypotension, nodal arrhythmia, syncope, tachycardia, thrombophlebitis (IV)
Central nervous system: Dizziness, drowsiness, dysarthria, headache, loss of consciousness, seizure, voice disorder
Dermatologic: Diaphoresis, skin rash, urticaria
Gastrointestinal: Diarrhea, dysphagia, flatulence, increased peristalsis, nausea, salivation, stomach cramps, vomiting
Genitourinary: Urinary urgency
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Neuromuscular & skeletal: Arthralgia, fasciculations, laryngospasm, muscle cramps, muscle spasm, weakness
Ophthalmic: Lacrimation, miosis
Respiratory: Bronchospasm, dyspnea, exacerbation of asthma, increased bronchial secretions, respiratory depression, respiratory paralysis
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.
• 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.
• Myasthenia gravis: 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.
• 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.
• Elderly: Use with caution and monitor for a longer period. Elderly patients experience slower spontaneous recovery from neuromuscular blocking agents.
ECG, blood pressure, and heart rate especially with IV use; 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 vital signs for 30 minutes and continuous clinical assessment for 15 to 30 minutes after administration (Saunders, 2005).
Pregnancy Risk Factor
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 near-term pregnant women. 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 women; however, if an acetylcholinesterase inhibitor is needed during pregnancy, another agent may be preferred (Massey 2014; Norwood 2014; Silvestri 2012).
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience insomnia, dry mouth, headache, nausea, or vomiting. Have patient report immediately to prescriber severe dizziness, passing out, tachycardia, bradycardia, abnormal heartbeat, shortness of breath, swelling in the arms or legs, muscle weakness, twitching, flushing, or shivering (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: cholinergic muscle stimulants
- Neostigmine Bromide (AHFS Monograph)
- Neostigmine Methylsulfate (AHFS Monograph)
- Neostigmine Methylsulfate Injection (FDA)