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Pyridostigmine

Class: Parasympathomimetic (Cholinergic) Agents
- Anticholinesterase Agents
VA Class: AU300
CAS Number: 101-26-8
Brands: Mestinon, Regonol

Medically reviewed by Drugs.com on May 18, 2020. Written by ASHP.

Warning

    Military Use for Soman Poisoning Prophylaxis
  • Use of pyridostigmine alone is not protective against soman effects. Efficacy depends on rapid use of nerve agent antidotes (i.e., atropine and pralidoxime) following nerve agent exposure.

  • Protective garments (e.g., masks, hoods, overgarments) specifically designed for protection from chemical nerve agents are the primary means of protection against nerve agent exposure; do not rely solely on pretreatment with pyridostigmine, atropine, and pralidoxime to provide complete protection.

  • Do not administer pyridostigmine after soman exposure. Discontinue at first sign of nerve agent poisoning; may exacerbate effects of a sublethal exposure.

    Experience of Health Care Personnel
  • Pyridostigmine should be administered by IV injection only by adequately trained individuals familiar with the drug’s actions, characteristics, and risks.

Introduction

Reversible anticholinesterase agent.

Uses for Pyridostigmine

Myasthenia Gravis

Symptomatic management of myasthenia gravis to improve muscle strength.

Following oral administration of a conventional preparation, onset of effect occurs within about 15–30 minutes and duration is about 3–4 hours.

Experts state that pyridostigmine should be part of the initial treatment in most patients with myasthenia gravis. Although symptomatic improvement can usually be achieved, additional treatment with corticosteroids or other immunosuppressive agents may be required.

Reversal of Neuromuscular Blockade

Reversal of the effects of nondepolarizing neuromuscular blocking agents (e.g., atracurium, cisatracurium, pancuronium, rocuronium, vecuronium).

Use in conjunction with an anticholinergic agent (atropine sulfate or glycopyrrolate) to counteract adverse muscarinic effects (e.g., bradycardia, bradyarrhythmias, increased secretions, bronchoconstriction).

Not effective and should not be used for reversal of depolarizing neuromuscular blocking agents (e.g., succinylcholine).

Chemical Warfare Agent Poisoning

Preexposure prophylaxis against lethal effects of soman nerve agent poisoning in military combat personnel.

Used in conjunction with standard treatment of nerve agent poisoning (i.e., atropine and pralidoxime chloride) and other protective measures (e.g., masks, hoods, overgarments).

Discontinue use at first indication of nerve agent poisoning. Not for use after exposure to soman; not expected to be effective after such exposure and may exacerbate effects of sublethal exposure. (See Military Use for Soman Poisoning Prophylaxis in Boxed Warning.)

Pyridostigmine Dosage and Administration

General

Myasthenia Gravis

  • Individualize dosage and frequency of administration. Minimize adverse effects with precise dosage adjustment.

  • Dosage requirements may vary from day to day, according to remissions and exacerbations of the disease and physical and emotional condition of the patient.

  • Treat mild exacerbations by increasing dosage under medical supervision as long as increase produces symptomatic improvement.

  • Complete restoration of muscle strength is rare; do not attempt to relieve all symptoms by increasing dosage above maximum response level.

  • Individual muscle groups may respond differently to the same dose; may produce weakness in one while increasing strength in another.

Reversal of Neuromuscular Blockade

  • Administer only by trained clinicians experienced in the use of neuromuscular blocking agents and their reversal agents.

  • Always have atropine and medications to treat shock readily available in case of hypersensitivity reaction.

  • Administer an anticholinergic agent (e.g., atropine sulfate) in conjunction with pyridostigmine to counteract adverse muscarinic effects (e.g., excessive secretions, bradycardia).

  • Monitor muscle twitch response to peripheral nerve stimulation; administer pyridostigmine after spontaneous recovery of neuromuscular function begins. Satisfactory reversal is evident by adequate voluntary respiration, respiratory measurements, and use of a peripheral nerve stimulator device.

  • Patient must be well ventilated; maintain patent airway and manual or mechanical ventilation until complete recovery of normal respiration is assured. Recurrence of paralysis unlikely after satisfactory reversal attained.

Chemical Warfare Agent Poisoning

  • Administer orally prior to an expected exposure to soman (i.e., when under the threat of a nerve agent attack). Do not take after exposure to soman.

  • If taken immediately before or at the same time as soman poisoning, pyridostigmine is not likely to be effective and may exacerbate the effects of a sublethal exposure.

Administration

Administer orally or by IV injection. Also has been administered by IM injection, but manufacturer of currently available injectable preparation states that this injection is for IV use only.

Oral Administration

Administer orally (as conventional tablets, extended-release tablets, or oral solution).

Oral solution may be useful for children and other patients who have difficulty swallowing or who require precise dosage adjustments not possible with tablets.

Extended-release tablets (Mestinon Timespan) are designed to slowly release drug for a prolonged duration of action; the immediate effect of a 180-mg extended-release tablet is similar to that of a 60-mg conventional tablet, but duration is about 2.5 times longer. Extended-release tablets generally used only at bedtime for patients who awaken at night or in the early morning with impairing weakness. May use extended-release tablets concurrently with conventional preparations to achieve optimum control.

NG Tube

May administer oral solution through nasogastric tube.

IV Administration

Administer by IV injection. (See General under Dosage and Administration.)

Dosage

Pediatric Patients

Myasthenia Gravis
Oral

Neonates: 5 mg every 4–6 hours has been used. (See Pediatric Use under Cautions.)

Children: 7 mg/kg daily (administered in 5–6 divided doses) has been used. (See Pediatric Use under Cautions.)

IV or IM

Neonates: 0.05–0.15 mg/kg (maximum single dose of 10 mg) every 4–6 hours has been used. (See Pediatric Use under Cautions.)

Children: 0.05–0.15 mg/kg (maximum single dose of 10 mg) every 4–6 hours has been used. (See Pediatric Use under Cautions.)

Adults

Myasthenia Gravis
Oral

Initiate with low dosage (usually 60 mg 3 times daily as conventional tablets or oral solution). May gradually increase as needed at intervals of ≥48 hours to provide maximum relief of symptoms.

Adjust dosage of conventional tablets or oral solution so larger doses are taken at times of greatest fatigue (e.g., 30–45 minutes before meals to assist patients who have difficulty eating).

Usual daily maintenance dosage ranges from 60 mg to 1.5 g (average 600 mg).

Extended-release tablets: Manufacturer suggests dosage of 180–540 mg 1–2 times daily (with ≥6 hours between doses). However, extended-release dosage form is generally used only at bedtime in patients who awaken at night or in the early morning with impairing weakness.

Oral dosage changes may take several days to produce results. When a further increase in dosage produces no corresponding increase in muscle strength, reduce dosage to the previous level.

Dosage requirements may vary from day to day.

IV or IM

When administered parenterally, approximately 1/30 of usual oral dose has been given by IM or very slow IV injection; however, currently available parenteral preparation (Regonol) not FDA-labeled for treatment of myasthenia gravis.

Reversal of Neuromuscular Blockade
IV

0.1–0.25 mg/kg. Give concurrently with or immediately after 0.6–1.2 mg IV atropine sulfate (or an equipotent dose of glycopyrrolate).

Full recovery usually occurs within 15 minutes but may require ≥30 minutes.

Additional doses of pyridostigmine not recommended if reversal is inadequate; instead, manage with manual or mechanical ventilation until adequate recovery occurs.

Chemical Warfare Agent Poisoning
Preexposure Prophylaxis for Soman Poisoning
Oral

30 mg every 8 hours beginning several hours prior to anticipated exposure.

Discontinue at first sign of nerve agent poisoning; immediately treat with atropine and pralidoxime.

Effects of use for >14 consecutive days not established; evaluate continuation of prophylaxis based on likelihood of exposure to soman.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Lower dosages may be required; carefully titrate dosage.

Geriatric Patients

Careful dosage selection recommended due to possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Pyridostigmine

Contraindications

  • Known hypersensitivity to anticholinesterase agents.

  • Mechanical obstruction of the intestinal or urinary tract.

Warnings/Precautions

Warnings

Cholinergic Crisis

Overdosage may result in cholinergic crisis (e.g., excessive salivation and sweating, miosis, nausea, vomiting, diarrhea, bradycardia or tachycardia, hypotension or hypertension, confusion, seizures, coma, severe muscle weakness, paralysis); may result in death. If overdosage occurs, maintain adequate respiration and give IV atropine.

Myasthenic crisis due to increased disease severity also causes extreme muscle weakness; symptomatic differentiation from cholinergic crisis may be difficult. Time to onset of symptoms approximately 1 hour after dose suggests overdosage, while ≥3 hours after dose suggests underdosage or resistance is the more likely diagnosis.

If severe cholinergic reaction occurs, discontinue pyridostigmine immediately and institute appropriate therapy as indicated (e.g., atropine, medications to treat shock).

Excessive IV doses may produce depolarization block when administered at doses above therapeutic range to reverse nondepolarizing neuromuscular blocking agent effects. Therapeutic index (ratio of reversal dose to blocking dose) is approximately 1:6.

Concomitant Diseases

Use with caution in patients with bronchial asthma, COPD, bradycardia, or cardiac arrhythmias.

Preexposure Prophylaxis for Soman Poisoning

Do not administer pyridostigmine after soman exposure. Discontinue at first sign of nerve agent poisoning; may exacerbate effects of a sublethal soman exposure. (See Boxed Warning.)

Military personnel experiencing severe adverse effects (e.g., difficulty breathing, severe dizziness, loss of consciousness) associated with pyridostigmine use should temporarily discontinue the drug and immediately seek medical care.

Sensitivity Reactions

Bromide Sensitivity

Use caution in patients with known bromide sensitivity.

May cause skin rash, which usually disappears when pyridostigmine bromide is discontinued.

General Precautions

Electrolyte Imbalance

Conditions resulting in electrolyte imbalance (e.g., adrenocortical insufficiency) may alter neuromuscular blockade (enhance or inhibit) and interfere with postoperative restoration of neuromuscular function by pyridostigmine.

Specific Populations

Pregnancy

Safety during pregnancy not established. Risk of uterine irritability and induction of premature labor if anticholinesterase agents are given IV near term.

Category B (30-mg tablets for military use only).

Lactation

Not known whether pyridostigmine is distributed into milk. Safety during lactation not established. Caution advised if used in nursing women.

Pediatric Use

Although manufacturers state safety and efficacy not established in pediatric patients, has been used for treatment of juvenile myasthenia gravis.

Pyridostigmine bromide injection (e.g., Regonol) contains 1% benzyl alcohol. Manufacturer does not recommend use in neonates; AAP states that the presence of small amounts of this preservative in a commercially available injection should not proscribe its use when indicated in neonates. Consider combined daily intake of benzyl alcohol from all sources.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.

Substantially eliminated by the kidneys; may be useful to monitor renal function since geriatric patients are more likely to have decreased renal function.

Renal Impairment

Use with caution. Clearance may be decreased; dosage adjustments necessary in renal disease. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea, abdominal pain or cramps, dysmenorrhea, increased flatus, nausea, urinary urgency and frequency.

Interactions for Pyridostigmine

Specific Drugs

Drug

Interaction

Comments

Aminoglycosides (e.g., gentamicin, neomycin, streptomycin)

Possible prolongation of neuromuscular blockade or resistance to reversal if used in conjunction with nondepolarizing neuromuscular blocking agents

Use cautiously, if at all

Anesthetics, local or general

Interfere with neuromuscular transmission

Use cautiously, if at all

Antiarrhythmic agents

Interfere with neuromuscular transmission

Use cautiously, if at all

Atropine

Antagonizes muscarinic effects of pyridostigmine

Interaction used to therapeutic advantage to counteract muscarinic symptoms of pyridostigmine toxicity; however, atropine also may mask manifestations of pyridostigmine overdose and prevent early detection of cholinergic crisis

Bacitracin

Possible prolongation of neuromuscular blockade or resistance to reversal if used in conjunction with nondepolarizing neuromuscular blocking agents

β-Adrenergic blocking agents

Possible additive bradycardia

Possible inhibition of pyridostigmine efficacy in myasthenia gravis

Use concomitantly with caution; effects on patients with borderline heart failure or AV conduction disturbances not determined

Magnesium salts

Possible enhanced neuromuscular blockade

Consider possibility of interference with restoration of neuromuscular function by pyridostigmine

Mefloquine

Possible additive GI effects

Possible additive effects on atrial rate

Miotics, topical (e.g., physostigmine)

Possible additive effects; may cause or exacerbate problems with night vision

Neuromuscular blocking agents, depolarizing (e.g., succinylcholine)

Possible enhanced and/or prolonged neuromuscular blockade

Do not use for reversal of depolarizing neuromuscular blockade

When pyridostigmine is used for nerve agent prophylaxis in soldiers, use caution if a depolarizing neuromuscular blocking agent is administered during surgery

Neuromuscular blocking agents, nondepolarizing (e.g., atracurium, cisatracurium, pancuronium, rocuronium, vecuronium)

Antagonism of nondepolarizing muscle relaxant effects

Interaction used to therapeutic advantage to reverse muscle relaxation induced by neuromuscular blocking agents after surgery

May need to increase dosage of nondepolarizing agent in soldiers who received pyridostigmine

Opiate agonists

Possible exacerbation of pyridostigmine-induced bradycardia

Polymyxins (e.g., colistin, polymyxin B, sodium colistimethate)

Possible prolongation of neuromuscular blockade or resistance to reversal if used in conjunction with nondepolarizing neuromuscular blocking agents

Quinidine

Recurrent paralysis may occur if used in conjunction with nondepolarizing neuromuscular blocking agents

Tetracyclines

Possible prolongation of neuromuscular blockade or resistance to reversal if used in conjunction with nondepolarizing neuromuscular blocking agents

Pyridostigmine Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed from GI tract following oral administration; bioavailability is 10–20%.

Peak plasma concentrations occur 2.2 hours after oral ingestion of a 30-mg dose as conventional tablet.

Extended-release tablets reportedly release one-third of total dose immediately, then remainder over 8–12 hours; however, release may be erratic and unpredictable.

Onset

Following oral administration in patients with myasthenia gravis, 30–45 minutes.

Following IV injection in patients with myasthenia gravis, muscle strength increased in 2–5 minutes.

When used for postoperative reversal of nondepolarizing neuromuscular blocking agent effects, time to peak effect is dose-dependent; with 0.25-mg/kg dosage, return of twitch height to 90% of control occurs within about 6 minutes. At lower dosages, full recovery usually occurs within 15 minutes; may require ≥30 minutes in some patients.

Duration

Duration of effect varies in patients with myasthenia gravis. Effects generally persist for 3–6 hours for conventional oral tablets, about 8–12 hours for extended-release tablets, and about 2–3 hours for IV injection.

Distribution

Extent

Distributed into most tissues, except brain, intestinal wall, fat, and thymus.

Crosses the placenta; not known whether distributed into milk.

Elimination

Metabolism

Metabolized via hydrolysis by cholinesterases and by microsomal enzymes in the liver.

Elimination Route

Excreted in urine, principally as unchanged drug (80–90%).

Half-life

Conventional oral tablets: 3 hours.

IV: 1.05–1.86 hours.

Special Populations

Patients with severe myasthenia gravis metabolize and excrete pyridostigmine faster than patients with milder forms of the disease.

Anephric patients: Half-life 6.3 hours; clearance decreased by 75%.

Geriatric patients (71–85 years of age): Plasma clearance decreased 30%, but half-life is unchanged.

No information available on pyridostigmine pharmacokinetics in patients with hepatic impairment.

Stability

Storage

Oral

Conventional 60-mg Tablets and Extended-release Tablets

25°C (may be exposed to 15–30°C).

Extended-release tablets are hygroscopic; tablets may become mottled, but this does not affect potency.

Conventional 30-mg Tablets for Military Use

2–8°C; protect from light. Discard unrefrigerated unit-dose packages after 3 months.

Oral Solution

25°C (may be exposed to 15–30°C).

Parenteral

Injection

25°C (may be exposed to 15–30°C). Protect from light.

Actions

  • Analog of neostigmine, but pyridostigmine may have a longer duration of action and fewer adverse GI effects.

  • Reversibly inhibits acetylcholinesterase, thereby prolonging and exaggerating the effects of acetylcholine. Has direct cholinomimetic effect on skeletal muscle.

  • Produces generalized cholinergic responses including miosis, bradycardia, increased tonus of intestinal musculature, constriction of bronchi and ureters, and stimulation of secretion by salivary and sweat glands.

  • At sufficiently high dosage, directly blocks action at autonomic ganglia, causes CNS stimulation followed by CNS depression, and, ultimately, depolarization block.

  • Blocks nerve agent soman from access to acetylcholinesterase active sites, protecting the enzyme from irreversible inhibition.

Advice to Patients

  • Patients with myasthenia gravis: importance of carefully following prescribed dosage instructions.

  • Advise military personnel to take pyridostigmine as directed by chain of command for preexposure prophylaxis for possible soman poisoning; advise not to take pyridostigmine immediately before (when attack alarm is given), during, or after exposure to soman. Importance of discontinuing pyridostigmine and following instructions provided in pyridostigmine patient information for treatment (e.g., atropine, pralidoxime) if soman poisoning occurs. Advise military personnel that if they experience serious adverse effects (e.g., difficulty breathing, severe dizziness, loss of consciousness), to temporarily discontinue the drug and immediately seek medical care. Advise such individuals that pyridostigmine alone is not protective against soman poisoning; the primary means of protection against nerve agent exposure is wearing protective garments (e.g., masks, hoods, overgarments) designed for this use. Importance of discarding 30-mg tablets 3 months after date of issue.

  • Importance of informing clinician of any allergy to bromide or anticholinesterase drugs.

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Pyridostigmine bromide 30-mg immediate-release tablets are for military use only.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Pyridostigmine Bromide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Solution

60 mg/5 mL

Mestinon Oral Solution

Bausch

Tablets, immediate-release

60 mg*

Mestinon (scored)

Bausch

Pyridostigmine Bromide Tablets

Tablets, extended-release

180 mg*

Mestinon Timespan (scored)

Bausch

Pyridostigmine Bromide Extended-release Tablets

Parenteral

Injection

5 mg/mL

Regonol

Sandoz

AHFS DI Essentials™. © Copyright 2021, Selected Revisions May 18, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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