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Neostigmine

Pronunciation

Pronunciation

(nee oh STIG meen)

Index Terms

  • Neostigmine Bromide
  • Neostigmine Methylsulfate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Injection, as methylsulfate:

Prostigmin: 0.5 mg/mL (1 mL, 10 mL)

Generic: 0.5 mg/mL (10 mL); 1 mg/mL (10 mL)

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)

Tablet, Oral, as bromide:

Prostigmin: 15 mg [DSC] [scored]

Brand Names: U.S.

  • Bloxiverz
  • Prostigmin

Pharmacologic Category

  • Acetylcholinesterase Inhibitor

Pharmacology

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

Absorption

Oral: Poor (~1% to 2%)

Distribution

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

Metabolism

Hepatic

Excretion

Urine (50% as unchanged drug)

Onset of Action

IM: 20 to 30 minutes; Oral: 1 to 2 hours

Duration of Action

IM: 2.5 to 4 hours

Half-Life Elimination

IM: Adults: 51 to 90 minutes

IV: Infants 2 to 10 months: Mean: 39 ± 5 minutes; Children 1 to 6 years: Mean: 48 ± 16 minutes; Adults: 24 to 113 minutes

Oral: Adults: 42 to 60 minutes

Protein Binding

15% to 25%

Special Populations: Renal Function Impairment

Renal function impairment: Elimination half-life prolonged in anephric patients

Special Populations: Children

Elimination half-life may be decreased; clearance rate may be increased

Use: Labeled Indications

Myasthenia gravis (excluding Bloxiverz): Symptomatic control of myasthenia gravis

Postoperative bladder distention/Urinary retention (excluding Bloxiverz and Prostigmin tablets): Prevention and treatment of postoperative bladder distention and urinary retention after mechanical obstruction has been excluded.

Reversal of nondepolarizing muscle relaxants (excluding Prostigmin tablets): Reversal of effects of nondepolarizing neuromuscular blocking agents (eg, tubocurarine, or pancuronium) after surgery.

Contraindications

Hypersensitivity to neostigmine or any component of the formulation; history of reaction to bromides (tablets only); peritonitis or mechanical obstruction of the intestinal or urinary tract

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.

Dosing: Adult

Note: Neostigmine (Prostigmin) tablets have been discontinued in the US for more than 1 year.

Myasthenia gravis: Diagnosis (off-label use): IM: 0.02 mg/kg as a single dose

Myasthenia gravis: Treatment:

Manufacturer’s labeling:

Oral: Usual dose: 150 mg administered over a 24-hour period; interval between doses is of paramount importance and therapy is frequently required day and night. Dosage range: 15 to 375 mg daily in divided doses.

IM, SubQ: 0.5 mg; subsequent dosing based on individual patient response

Alternative recommendations (off-label dosing):

Oral: Initial: 15 mg every 8 hours; may increase every 1 to 2 days up to 375 mg daily maximum; interval between doses must be individualized to maximal response

IM, IV, SubQ: 0.5 to 2.5 mg every 1 to 3 hours as needed up to 10 mg/24 hours maximum

Reversal of nondepolarizing neuromuscular blockade after surgery:

Bloxiverz: IV: 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.

Generic products: IV: 0.5 to 2 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 in a separate syringe several minutes before neostigmine.

Postoperative urinary retention: IM, SubQ:

Prevention: 0.25 mg as soon as possible after operation; repeat every 4 to 6 hours for 2 to 3 days

Treatment: 0.5 mg; if urination does not occur within an hour, patient should be catheterized. After the bladder has emptied or patient has voided, continue 0.5 mg every 3 hours for at least 5 doses.

Postoperative bladder distention: IM, SubQ:

Prevention: 0.25 mg as soon as possible after operation; repeat every 4 to 6 hours for 2 to 3 days

Treatment: 0.5 mg as needed

Acute colonic pseudo-obstruction (Ogilvie syndrome) (off-label use): Adults: 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: Diagnosis (off-label use): Children: IM: 0.025 to 0.04 mg/kg as a single dose

Myasthenia gravis: Treatment (off-label use): Children:

Oral: 2 mg/kg/day, not to exceed 375 mg daily

IM, IV, SubQ: 0.01 to 0.04 mg/kg every 2 to 4 hours as needed

Reversal of nondepolarizing neuromuscular-blocking agents (NMBAs) after surgery (Bloxiverz): Infants, Children, and Adolescents: IV: Refer to adult dosing.

Note: An anticholinergic agent (atropine or glycopyrrolate) should be given prior to or in conjunction with 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.

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling; however, the following adjustments have been recommended (Aronoff, 2007): Adults: Oral:

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

No dosage adjustment provided in manufacturer’s labeling.

Administration

Tablets (neostigmine bromide): Administer without regard to food. Consider giving larger portions of the daily dose around fatigue prone times (eg, mealtimes, afternoons).

Injectable (neostigmine methylsulfate): Administer IM, SubQ, or 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).

Compatibility

Stable in D5LR, D51/4NS, D51/2NS, D5NS, D5W, D10W, LR, NS.

Storage

Injection: 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.

Tablets: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Anticholinergic Agents: Acetylcholinesterase Inhibitors may diminish the therapeutic effect of Anticholinergic Agents. Anticholinergic Agents may diminish the therapeutic effect of Acetylcholinesterase Inhibitors. 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: Arrhythmias (especially bradycardia), AV block, cardiac arrest, flushing, hypotension, nodal rhythm, nonspecific ECG changes, syncope, tachycardia

Central nervous system: Convulsions, dizziness, drowsiness, dysarthria, dysphonia, headache, loss of consciousness

Dermatologic: Skin rash, thrombophlebitis (IV), urticaria

Gastrointestinal: Diarrhea, dysphagia, flatulence, hyperperistalsis, nausea, salivation, stomach cramps, vomiting

Genitourinary: Urinary urgency

Neuromuscular & skeletal: Arthralgias, fasciculations, muscle cramps, spasms, weakness

Ocular: Lacrimation, small pupils

Respiratory: Bronchiolar constriction, bronchospasm, dyspnea, increased bronchial secretions, laryngospasm, respiratory arrest, respiratory depression, respiratory muscle paralysis

Miscellaneous: Allergic reactions, anaphylaxis, diaphoresis increased

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 urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia, and anaphylaxis. 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 the dose of neostigmine 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.

• 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: Recovery of neuromuscular activity occurs more rapidly with smaller doses of cholinesterase inhibitors in infants and children. However, infants and small children may be at greater risk of complications from incomplete reversal of neuromuscular blockade due to decreased respiratory reserve. The risks associated with incomplete reversal outweigh any risk from giving higher doses of neostigmine. Since the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate, the effects of an anticholinergic agent (eg, atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension.

• 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 Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted; 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 (Norwood, 2013; Silvestri, 2012).

Patient Education

• 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 dyspepsia, diarrhea, headache, nausea, or sialorrhea. Have patient report immediately to prescriber severe dizziness, syncope, vision changes, bradycardia, arrhythmia, angina, dyspnea, asthenia, fasciculations, or change in balance (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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