neostigmine/glycopyrrolate (Rx)

Brand and Other Names:Prevduo

Dosing & Uses

AdultPediatric

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

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Interactions

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                    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

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                    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
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                    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.

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                    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)
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                    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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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

                    FormularyPatient Discounts

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                    The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
                    PA Prior Authorization
                    Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
                    QL Quantity Limits
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                    Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.