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ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(peer id oh STIG meen)

Generic Available (U.S.)

Yes: Tablet

Index Terms

• Pyridostigmine Bromide

Brand Names: U.S.

• Mestinon®
• Mestinon® Timespan®
• Regonol®

Brand Names: Canada

• Mestinon®
• Mestinon®-SR

Pharmacologic Category

• Acetylcholinesterase Inhibitor

Pharmacologic Category Synonyms

• Cholinesterase Inhibitor

Use: Labeled Indications

Symptomatic treatment of myasthenia gravis; antagonism of nondepolarizing neuromuscular blockers

Military use: Pretreatment for Soman nerve gas exposure

Pregnancy Risk Factor

B

Pregnancy Considerations

Safety has not been established for use during pregnancy. The potential benefit to the mother should outweigh the potential risk to the fetus. When pyridostigmine is needed in myasthenic mothers, giving dose parenterally 1 hour before completion of the second stage of labor may facilitate delivery and protect the neonate during the immediate postnatal state.

Lactation

Enters breast milk/compatible

Breast-Feeding Considerations

Neonates of myasthenia gravis mothers may have difficulty in sucking and swallowing (as well as breathing). Neonatal pyridostigmine may be indicated by symptoms (confirmed by edrophonium test).

Contraindications

Hypersensitivity to pyridostigmine, bromides, or any component of the formulation; GI or GU obstruction

Warnings/Precautions

Boxed warnings:

• Experienced personnel: Regonol® injection: See “Dosage form specific issues” below.

Concerns related to adverse effects:

• Anticholinesterase insensitivity: For brief or prolonged periods, anticholinesterase insensitivity can develop.

• Cholinergic effects: Discontinue if symptoms of excess cholinergic activity (eg, salivation, sweating, urinary incontinence); overdosage may result in cholinergic crisis, which must be distinguished from myasthenic crisis.

• Hypersensitivity reactions: Have atropine and epinephrine ready to treat hypersensitivity reactions.

Disease-related concerns:

• Asthma or bronchospastic disease: Use with extreme caution in patients with asthma or bronchospastic disease.

• Cardiovascular disease: Use with caution in patients with bradycardia or cardiac arrhythmias.

• GI disease: Use with caution in patients with GI disease, including peptic ulcer disease.

• 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.

• Seizure disorder: Use with caution in patients with a history of seizure disorder.

Dosage form specific issues:

• Experienced personnel: Regonol® injection: Contains 1% benzyl alcohol as the preservative; not intended for use in newborns. [U.S. Boxed Warning]: Must be administered by trained personnel.

Adverse Reactions

Frequency not defined.

Cardiovascular: Arrhythmias (especially bradycardia), AV block, cardiac arrest, decreased carbon monoxide, flushing, hypotension, nodal rhythm, nonspecific ECG changes, syncope, tachycardia

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

Dermatologic: Skin rash, thrombophlebitis (I.V.), urticaria

Gastrointestinal: Abdominal pain, diarrhea, dysphagia, flatulence, hyperperistalsis, nausea, salivation, stomach cramps, vomiting

Genitourinary: Urinary urgency

Neuromuscular & skeletal: Arthralgia, dysarthria, fasciculations, muscle cramps, myalgia, spasms, weakness

Ocular: Amblyopia, lacrimation, small pupils

Respiratory: Bronchial secretions increased, bronchiolar constriction, bronchospasm, dyspnea, laryngospasm, respiratory arrest, respiratory depression, respiratory muscle paralysis

Miscellaneous: Allergic reactions, anaphylaxis, diaphoresis increased

Metabolism/Transport Effects

None known.

Drug Interactions

Beta-Blockers: Acetylcholinesterase Inhibitors may enhance the bradycardic effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Risk C: Monitor therapy

Cholinergic Agonists: Acetylcholinesterase Inhibitors may enhance the adverse/toxic effect of Cholinergic Agonists. Risk C: Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Acetylcholinesterase Inhibitors. Increased muscular weakness may occur. Risk C: Monitor therapy

Dipyridamole: May diminish the therapeutic effect of Acetylcholinesterase Inhibitors. Risk C: Monitor therapy

Methocarbamol: May diminish the therapeutic effect of Pyridostigmine. Risk C: Monitor therapy

Neuromuscular-Blocking Agents (Nondepolarizing): Acetylcholinesterase Inhibitors may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents (Nondepolarizing). Risk C: 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. Risk D: Consider therapy modification

Storage

Injection: Protect from light.

Tablet:

30 mg: Store under refrigeration at 2°C to 8°C (36°F to 46°F). Protect from light. Stable at room temperature for up to 3 months.

Mestinon®: Store at 25°C (77°F). Protect from moisture.

Compatibility

Y-site administration: Compatible: Heparin, hydrocortisone sodium succinate, potassium chloride, vitamin B complex with C.

Compatibility in syringe: Compatible: Glycopyrrolate.

Mechanism of Action

Inhibits destruction of acetylcholine by acetylcholinesterase which facilitates transmission of impulses across myoneural junction

Pharmacodynamics/Kinetics

Onset of action: Oral, I.M.: 15-30 minutes; I.V. injection: 2-5 minutes

Duration: Oral: Up to 6-8 hours (due to slow absorption); I.V.: 2-3 hours

Absorption: Oral: Very poor

Distribution: 19 ± 12 L

Metabolism: Hepatic

Bioavailability: 10% to 20%

Half-life elimination: 1-2 hours; Renal failure: ≤6 hours

Excretion: Urine (80% to 90% as unchanged drug)

Dosage

Myasthenia gravis:

Oral:

Children: 7 mg/kg/24 hours divided into 5-6 doses

Adults: Highly individualized dosing ranges: 60-1500 mg/day, usually 600 mg/day divided into 5-6 doses, spaced to provide maximum relief

Sustained release formulation: Highly individualized dosing ranges: 180-540 mg once or twice daily (doses separated by at least 6 hours); Note: Most clinicians reserve sustained release dosage form for bedtime dose only.

I.M., slow I.V. push:

Children: 0.05-0.15 mg/kg/dose

Adults: To supplement oral dosage pre- and postoperatively during labor and postpartum, during myasthenic crisis, or when oral therapy is impractical: ~1/30th of oral dose; observe patient closely for cholinergic reactions

or

I.V. infusion: Initial: 2 mg/hour with gradual titration in increments of 0.5-1 mg/hour, up to a maximum rate of 4 mg/hour

Reversal of nondepolarizing muscle relaxants: Note: Atropine sulfate (0.6-1.2 mg) I.V. immediately prior to pyridostigmine to minimize side effects: I.V.:

Children: Dosing range: 0.1-0.25 mg/kg/dose*

Adults: 0.1-0.25 mg/kg/dose; 10-20 mg is usually sufficient*

*Full recovery usually occurs ≤15 minutes, but ≥30 minutes may be required

Pretreatment for Soman nerve gas exposure (military use): Oral: Adults: 30 mg every 8 hours beginning several hours prior to exposure; discontinue at first sign of nerve agent exposure, then begin atropine and pralidoxime

Dosage adjustment in renal dysfunction: Lower dosages may be required due to prolonged elimination; no specific recommendations have been published

Administration: Oral

Do not crush sustained release tablet.

Administration: I.V. Detail

pH: 5

Monitoring Parameters

Observe for cholinergic reactions, particularly when administered I.V.

Test Interactions

Increased aminotransferase [ALT/AST] (S), increased amylase (S)

Patient Education

This drug will not cure myasthenia gravis, but may help reduce symptoms. Take extended release tablets at bedtime; do not chew or crush extended release tablets. May cause dizziness, drowsiness, or hypotension; vomiting or loss of appetite; or diarrhea. Report persistent abdominal discomfort; significantly increased salivation, sweating, tearing, or urination; flushed skin; chest pain or palpitations; acute headache; unresolved diarrhea; excessive fatigue, insomnia, dizziness, or depression; increased muscle, joint, or body pain; vision changes or blurred vision; or shortness of breath or wheezing.

Geriatric Considerations

Many elderly may have pulmonary or cardiovascular diseases which will require cautious use of pyridostigmine.

Anesthesia and Critical Care Concerns/Other Considerations

Clinical Pearls/Comments: For reversal of neuromuscular blockade, atropine or glycopyrrolate must be administered with pyridostigmine to minimize its cholinergic effects. For patients with myasthenia gravis, extended release products may be preferred at bedtime for patients who are very weak upon rising in the morning.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Dysphagia.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May rarely cause dysphoria or drowsiness

Mental Health: Effects on Psychiatric Treatment

None reported; but mouth watering is common and may be additive to the sialorrhea associated with clozapine therapy

Nursing: Physical Assessment/Monitoring

When used to reverse neuromuscular block (anesthesia or excessive acetylcholine), monitor patient safety until full return of neuromuscular functioning. Assess bladder and sphincter adequacy prior to treatment. Monitor for cholinergic crisis.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution, as bromide:

Regonol®: 5 mg/mL (2 mL) [contains benzyl alcohol]

Syrup, oral, as bromide:

Mestinon®: 60 mg/5 mL (480 mL) [contains ethanol 5%, sodium benzoate; raspberry flavor]

Tablet, oral, as bromide: 60 mg

Mestinon®: 60 mg [scored]

Tablet, sustained release, oral, as bromide:

Mestinon® Timespan®: 180 mg [scored]

Pricing: U.S. (www.drugstore.com)

Syrup (Mestinon)

60 mg/5 mL (240): $90.99

Tablet, controlled release (Mestinon)

180 mg (30): $126.00

Tablets (Mestinon)

60 mg (30): $97.00

Tablets (Pyridostigmine Bromide)

60 mg (30): $21.99

References

Dunn MA and Sidell FR, “Progress in Medical Defense Against Nerve Agents,” JAMA, 1989, 262(5):649-52.

Keeler JR, Hurst CG, and Dunn MA, “Pyridostigmine Used as a Nerve Agent Pretreatment Under Wartime Conditions,” JAMA, 1991, 266(5):693-5.

Saltis LM, Martin BR, Traeger SM, et al, “Continuous Infusion of Pyridostigmine in the Management of Myasthenic Crisis,” Crit Care Med,1993, 21(6):938-40.

Sidell FR and Borak J, “Chemical Warfare Agents: II. Nerve Agents,” Ann Emerg Med, 1992, 21(7):865-71.

International Brand Names

• Amygra (PK)
• Antilon (TW)
• Astinon (PH)
• Brostagin (PL)
• Distinon (IN)
• Kalymin (BG, DE, EE, RU)
• Mestinon (AE, AR, AT, AU, BB, BE, BH, BM, BR, BS, BZ, CH, CN, CO, CR, CY, CZ, DK, DO, EG, ES, FI, FR, GB, GH, GR, GT, GY, HK, HN, HR, HU, ID, IE, IL, IQ, IR, IT, JM, JO, KP, KW, LB, LU, LY, MX, MY, NI, NO, OM, PA, PE, PH, PL, PT, PY, QA, SA, SE, SG, SR, SV, SY, TH, TR, TT, TW, TZ, UG, UY, VE, YE, ZM)
• Mestinon Retard (NL)
• Pyrimine (TH)
• Pyrinol (KP)
• Pyrinon (PH)

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Last full review/revision December 2011

Content last modified December 2011