Neostigmine

Generic name: neostigmine systemic

Brand names: Prostigmin, Prostigmin Bromide, Bloxiverz

Reviewed by Medicine.com on February 17, 2020

Dosage Forms

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)

Solution Prefilled Syringe, Intravenous, as methylsulfate:

Generic: 3 mg/3 mL (3 mL)

Pharmacology

Mechanism of Action

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

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: Poor (~1% to 2%)

Distribution

Distribution: V_d: IV: 0.12 to 1.4 L/kg

Metabolism

Hepatic

Excretion

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

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 patients: 104.7 ± 64 minutes

Oral: Adults: 42 to 60 minutes

Protein Binding

15% to 25% to albumin

Use in Specific Populations

Special Populations: Renal Function Impairment

Elimination half-life prolonged in anephric patients.

Use: Labeled Indications

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

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.

Use: Off Label

Acute colonic pseudo-obstruction (Ogilvie’s syndrome)b

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.

Contraindications

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.

Dosage and Administration

Dosing: Adult

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:

US labeling:

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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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 (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 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:

Alternate dosing: Generic injectable products: Limited data available (Kliegman 2007; Nelson 1996): Infants and Children: 0.025 to 0.1 mg/kg/dose

Administration

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).

Storage

Injection:

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.

Drug Interactions

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

Adverse Reactions

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

Warnings/Precautions

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.
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.

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.
Elderly: Use with caution and monitor for a longer period. Elderly patients experience slower spontaneous recovery from neuromuscular blocking agents.

Monitoring Parameters

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

Pregnancy Risk Factor

Pregnancy Considerations

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).

Patient Education

What is this drug used for?

It is used to treat myasthenia gravis.
It is used to get back function in muscles after surgery.
It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

Trouble sleeping
Dry mouth
Headache
Nausea
Vomiting

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

Severe dizziness
Passing out
Fast heartbeat
Slow heartbeat
Abnormal heartbeat
Shortness of breath
Swelling in the arms or legs
Muscle weakness
Twitching
Flushing
Shivering
Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated February 8, 2020.