Dosing & Uses
Dosage Forms & Strengths
neostigmine/glycopyrrolate
injectable solution
- (3mg/0.6mg)/3mL (single-dose prefilled syringe)
Nondepolarizing Neuromuscular Blockade Reversal
Indicated for nondepolarizing neuromuscular blocking agents (NMBAs) reversal after surgery, while decreasing the peripheral muscarinic effects (eg, bradycardia and excessive secretions) associated with cholinesterase inhibition following NMBA reversal administration
0.03-0.07 mg/kg neostigmine (0.006-0.014 mg/kg of glycopyrrolate) IV will achieve a train-of-four (TOF) twitch ratio of 90% (TOF0.9) within 10-20 min of administration
Neostigmine-induced bradycardia is minimized due to the included 0.2 mg of glycopyrrolate per 1 mg neostigmine
Select dose based on extent of spontaneous recovery that has occurred at time of administration, half-life of NMBA being reversed, and whether there is a need to rapidly reverse the NMBA
Use 0.03 mg/kg dose of neostigmine (0.006 mg/kg of glycopyrrolate) for:
- Reversal of NMBAs with shorter half-lives (eg, rocuronium) or
- When first twitch response to TOF stimulus is >10% of baseline or
- When a second twitch is present
Use 0.07 mg/kg dose of neostigmine (0.014 mg/kg of glycopyrrolate) for:
- Reversal of NMBAs with longer half-lives (eg, vecuronium, pancuronium) or
- When first twitch response is relatively weak (ie, not substantially >10% of baseline) or
- There is a need for more rapid recovery
- Recommended maximum total dose is 0.07 mg/kg of neostigmine or up to a total of 5 mg of neostigmine, whichever is less
Dosage Modifications
Renal impairment
- No dosing adjustment necessary
- Closely monitor to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of neostigmine and glycopyrrolate
Hepatic impairment
- Neostigmine: Pharmacokinetics in patients with hepatic impairment not studied
- Neostigmine is metabolized by microsomal enzymes in the liver, while glycopyrrolate is mostly eliminated unchanged by the kidney
- No dosing adjustments necessary
Dosing Considerations
Before administration and until complete recovery, patient should be well ventilated and patent airway maintained
Satisfactory recovery: Evaluate adequacy of skeletal muscle tone and respiratory measurements in addition to response to peripheral stimulation
There must be a twitch response to first stimulus in train-of-four (TOF) of at least 10% of its baseline level (ie, response before administering NMBA, before administering neostigmine/glycopyrrolate)
Peripheral nerve stimulation devices capable of delivering a TOF stimulus are essential to effectively administering therapy
Continue to monitor TOF to evaluate the extent of recovery of neuromuscular function and if an additional dose of neostigmine/glycopyrrolate is necessary
Do NOT rely on TOF monitoring to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to ventilate and maintain a patent airway following tracheal extubation
Continue to monitor for adequacy of reversal from NMBAs for a period that ensures full recovery based on patient’s medical condition and pharmacokinetics of neostigmine and NMBA used
Dosage Forms & Strengths
neostigmine/glycopyrrolate
injectable solution
- (3mg/0.6mg)/3mL (single-dose prefilled syringe)
Nondepolarizing Neuromuscular Blockade Reversal
Indicated for nondepolarizing neuromuscular blocking agents (NMBAs) reversal after surgery, while decreasing the peripheral muscarinic effects (eg, bradycardia and excessive secretions) associated with cholinesterase inhibition following NMBA reversal administration
<2 years: Not recommended as blood pressure in these patients is sensitive to changes in heart rate
≥2 years
- 0.03-0.07 mg/kg neostigmine (0.006-0.014 mg/kg of glycopyrrolate) IV will achieve a train-of-four (TOF) twitch ratio of 90% (TOF0.9) within 10-20 min of administration
- Neostigmine-induced bradycardia is minimized due to the included 0.2 mg of glycopyrrolate per 1 mg neostigmine
- Select dose based on extent of spontaneous recovery that has occurred at time of administration, half-life of NMBA being reversed, and whether there is a need to rapidly reverse the NMBA
-
Use 0.03 mg/kg dose of neostigmine (0.006 mg/kg of glycopyrrolate) for:
- Reversal of NMBAs with shorter half-lives (eg, rocuronium) or
- When first twitch response to TOF stimulus is substantially >10% of baseline or
- When a second twitch is present
-
Use 0.07 mg/kg dose of neostigmine (0.014 mg/kg of glycopyrrolate) for:
- Reversal of NMBAs with longer half-lives (eg, vecuronium, pancuronium) or
- When first twitch response is relatively weak (ie., not substantially >10% of baseline) or
- There is a need for more rapid recovery
- Recommended maximum total dose is 0.07 mg/kg of neostigmine or up to a total of 5 mg of neostigmine, whichever is less
Dosage Modifications
Renal impairment
- No dosing adjustment necessary
- Closely monitor to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of neostigmine and glycopyrrolate
Hepatic impairment
- Neostigmine: Pharmacokinetics in patients with hepatic impairment not studied
- Neostigmine is metabolized by microsomal enzymes in the liver, while glycopyrrolate is mostly eliminated unchanged by the kidney
- No dosing adjustments necessary
Dosing Considerations
Before administration and until complete recovery, patient should be well ventilated and patent airway maintained
Satisfactory recovery: Evaluate adequacy of skeletal muscle tone and respiratory measurements in addition to response to peripheral stimulation
There must be a twitch response to first stimulus in train-of-four (TOF) of at least 10% of its baseline level (ie, response before administering NMBA, before administering neostigmine/glycopyrrolate)
Peripheral nerve stimulation devices capable of delivering a TOF stimulus are essential to effectively administering therapy
Continue to monitor TOF to evaluate the extent of recovery of neuromuscular function and if an additional dose of neostigmine/glycopyrrolate is necessary
Do NOT rely on TOF monitoring to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to ventilate and maintain a patent airway following tracheal extubation
Continue to monitor for adequacy of reversal from NMBAs for a period that ensures full recovery based on patient’s medical condition and pharmacokinetics of neostigmine and NMBA used
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
1-10%
≥1% (neostigmine)
- Bradycardia
- Hypotension
- Tachycardia/increase heart rate
- Dry mouth
- Nausea
- Postprocedural nausea
- Vomiting
- Incision site complication
- Pharyngolaryngeal pain
- Procedural complication
- Procedural pain
- Dizziness
- Headache
- Postoperative shivering
- Prolonged neuromuscular blockage
- Insomnia
- Dyspnea
- Oxygen desaturation <90%
- Pruritus
Frequency Not Defined
Glycopyrrolate
- Xerostomia (dry mouth)
- Urinary hesitancy and retention
- Blurred vision and photophobia due to mydriasis (dilation of the pupil)
- Cycloplegia
- Increased ocular tension
- Tachycardia
- Palpitation
- Decreased sweating
- Loss of taste
- Headache
- Nervousness
- Drowsiness
- Weakness
- Dizziness
- Insomnia
- Nausea
- Vomiting
- Impotence
- Suppression of lactation
- Constipation
- Bloated feeling
- Severe allergic reactions including anaphylactic/anaphylactoid reactions
- Hypersensitivity
- Urticaria, pruritus, dry skin, and other dermal manifestations
Postmarketing Reports
Neostigmine
- Allergic disorders: Allergic reactions, anaphylaxis
- Nervous system disorders: Convulsions, drowsiness, dysarthria, fasciculation, loss of consciousness, miosis, visual changes
- Cardiovascular disorders: Cardiac arrest, cardiac arrhythmias (A-V block, nodal rhythm), hypotension, nonspecific EKG changes, syncope
- Respiratory, thoracic, and mediastinal disorders: Bronchospasm; increased oral, pharyngeal and bronchial secretions; respiratory arrest; respiratory depression
- Skin and subcutaneous tissue disorders: Rash, urticaria
- Gastrointestinal disorders: Bowel cramps, diarrhea, flatulence, increased peristalsis
- Renal and urinary disorders: Urinary frequency
- Musculoskeletal and connective tissue disorders: Arthralgia, muscle cramps, spasms, weakness
- Miscellaneous: Diaphoresis, flushing
Glycopyrrolate
- Cardiovascular disorders: Cardiac arrhythmias (including bradycardia, ventricular tachycardia, ventricular fibrillation), cardiac arrest, hypertension, hypotension, heart block and QTc interval prolongation
- Respiratory, thoracic, and mediastinal disorders: Respiratory arrest
- Injection site reactions: Pruritus, edema, erythema, and pain at injection site
- Miscellaneous: Malignant hyperthermia
Warnings
Contraindications
Hypersensitivity to neostigmine
Peritonitis or mechanical obstruction of intestinal or urinary tract
Glaucoma; obstructive uropathy (eg, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (eg, achalasia, pyloroduodenal stenosis); paralytic ileus, intestinal atony of elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis
Cautions
Medications to treat anaphylaxis should be readily available
Large doses of neostigmine/glycopyrrolate administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction; reduce dose if recovery from neuromuscular blockade is nearly complete
It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine; both conditions result in extreme muscle weakness, but require radically different treatment
Glycopyrrolate may cause drowsiness or blurred vision; advise patients not to participate in activities requiring mental alertness, such as operate a motor vehicle or other machinery or perform hazardous work, until these issues resolve
Glycopyrrolate, may cause heat prostration (due to decreased sweating) in presence of fever, high environmental temperature, and/or during physical exercise, particularly in children and the elderly; advise patients to avoid exertion and high environmental temperature after receiving therapy
Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy; avoid use with these conditions
Cardiovascular cautions
- Neostigmine is associated with bradycardia; consider administering glycopyrrolate before neostigmine (eg, as separate products) in patients with bradycardia or in patients in whom bradycardia, a known risk of neostigmine, may cause hemodynamic instability
- Caution with coronary artery disease, congestive heart failure, cardiac arrhythmias, recent acute coronary syndrome, or hypertension
- Patients with acute cardiovascular conditions (eg, coronary artery disease, cardiac arrhythmias or recent acute coronary syndrome) may be at an increased risk of blood pressure and heart rate complications
- Owing to pharmacology of neostigmine as an acetylcholinesterase inhibitor, cardiovascular effects (eg, bradycardia, hypotension, dysrhythmia) would be anticipated
- Investigate any tachycardia before giving glycopyrrolate because an increase in heart rate may occur
Myasthenia gravis and hyperthyroidism
- Caution with myasthenia gravis and hyperthyroidism
- Patients with myasthenia gravis may be at an increased risk of blood pressure and heart rate complications
Ophthalmic cautions
- Advise patients with glaucoma to promptly seek medical care if they experience symptoms of acute angle closure glaucoma (pain and reddening of the eyes, accompanied by dilated pupils)
- Glycopyrrolate may cause drowsiness or blurred vision; advise patients not to participate in activities requiring mental alertness, such as operate a motor vehicle or other machinery or perform hazardous work until these issues resolve
Drug interactions overview
-
Neostigmine
- Pharmacokinetic interaction between neostigmine and other drugs not studied
- Caution when coadministered with other drugs which may alter activity of metabolizing enzymes or transporters
-
Glycopyrrolate
- Coadministration with other anticholinergics or medications with anticholinergic activity (eg, phenothiazines, antiparkinson drugs, tricyclic antidepressants) may intensify antimuscarinic effects and result in increased anticholinergic side effects
Pregnancy & Lactation
Pregnancy
Neostigmine
- There are no adequate or well-controlled studies of neostigmine in pregnant females
- Unknown whether neostigmine can cause fetal harm when administered to pregnant females or can affect reproductive capacity
- Anticholinesterase drugs, including neostigmine, may cause uterine irritability and induce premature labor when administered to pregnant females near term
Glycopyrrolate
- Limited data available with glycopyrrolate use during pregnancy have not identified a drug-associated risk of birth defects and miscarriage, however, most of the reported exposures occurred after the first trimester
-
Animal data
- Glycopyrrolate was administered orally in rats and intramuscularly in rabbits during organogenesis, no teratogenic effects were seen at 640-times and 10-times the maximum recommended human dose of 1 mg (on a mg/m2 basis), respectively
Lactation
Unknown whether neostigmine and glycopyrrolate are excreted in human milk
As with other anticholinergics, glycopyrrolate may suppress lactation
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Neostigmine
- Competitively inhibits action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation
- These peripheral cholinergic receptors are present in autonomic effector cells of smooth muscle, cardiac muscle, sinoatrial node, atrioventricular node, exocrine glands and, to a limited degree, in the autonomic ganglia
- Thus, it diminishes volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions
Glycopyrrolate
- Competitively inhibits action of acetylcholine on autonomic effectors innervated by postganglionic nerves
Absorption
Peak plasma time
- Glycopyrrolate (8 mcg/kg IM): 27.48 minutes
Peak plasma concentration
- Glycopyrrolate (8 mcg/kg IM): 3.47 mcg/L
AUC
- Glycopyrrolate (6 mcg/kg IV): 8.64 mcg·kg/L
- Glycopyrrolate (8 mcg/kg IM): 6.64 mcg·kg/L
Distribution
Vd
- Neostigmine: 0.12-1.4 L/kg
- Glycopyrrolate: 0.42 L/kg
Metabolism
Neostigmine: Microsomal enzymes in liver
Elimination
Clearance
- Neostigmine: 1.14-16.7 mL/min/kg
- Glycopyrrolate: 0.54 L/kg/hr
Half-life
- Neostigmine: 24-113 min
- Glycopyrrolate: 0.83 hr
Excretion
- Glycopyrrolate: Urine and bile (80%, unchanged)
Administration
IV Preparation
Remove prefilled syringe from plastic tray
Visually inspect syringe for any particles or discoloration
Twist off tip cap of syringe and discard
Expel air bubble by pushing plunger rod; adjust dose, if applicable
Connect prefilled syringe to an appropriate IV connection
Ensure prefilled syringe is securely attached to needle or needleless luer access device (NLAD)
Press plunger rod slowly to deliver medication through needle or needleless luer access device (NLAD) over a period of at least 1 minute
IV Administration
IV use only
Slowly inject over at least 1 minute
Remove prefilled syringe from needle or needleless luer access device (NLAD) and discard into appropriate receptacle; do NOT recap syringe
Monitoring
- Continue to monitor TOF to evaluate the extent of recovery of neuromuscular function and if an additional dose of neostigmine/glycopyrrolate is necessary
- Do NOT rely on TOF monitoring to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to ventilate and maintain a patent airway following tracheal extubation
- Continue to monitor for adequacy of reversal from NMBAs for a period that ensures full recovery based on patient’s medical condition and pharmacokinetics of neostigmine and NMBA used
Storage
Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F)
Protect from light
Store in carton until time of use
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