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  • CLASSES

    Myasthenia Gravis Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral and parenteral cholinesterase inhibitor
    Used for myasthenia gravis and reversal of neuromuscular blocking effects of nondepolarizing muscle relaxants as well as for military medical use as pretreatment for exposure to Soman nerve agent
    Longer duration of action and associated with fewer muscarinic effects compared to neostigmine

    COMMON BRAND NAMES

    Mestinon, Regonol

    HOW SUPPLIED

    Mestinon/Pyridostigmine/Pyridostigmine Bromide Oral Sol: 5mL, 60mg
    Mestinon/Pyridostigmine/Pyridostigmine Bromide Oral Tab ER: 180mg
    Mestinon/Pyridostigmine/Pyridostigmine Bromide Oral Tab: 30mg, 60mg
    Pyridostigmine/Pyridostigmine Bromide/Regonol Intramuscular Inj Sol: 1mL, 5mg
    Pyridostigmine/Pyridostigmine Bromide/Regonol Intravenous Inj Sol: 1mL, 5mg

    DOSAGE & INDICATIONS

    For the treatment of myasthenia gravis.
    NOTE: Failure of patients to show clinical improvement may reflect underdosage or overdosage. Overdosage of pyridostigmine may result in a life-threatening cholinergic crisis, which is characterized by increasing muscle weakness. Extreme muscle weakness is also characteristic of myasthenic crisis. Thus, differentiation on a symptomatic basis between cholinergic crisis and myasthenic crisis may be difficult. Differentiation is extremely important, as increases in pyridostigmine doses could have grave consequences in the presence of cholinergic crisis or refractory state.[64002]
    Oral dosage (regular-release 60 mg tablets or 60 mg/5 mL oral solution or syrup)
    Adults

    600 mg/day PO in divided doses spaced to provide maximum relief when maximum strength is needed. Adjust the dosage to the needs of the individual patient; dosage range, 60 to 1,500 mg/day.[32948] [64002]

    Infants†, Children†, and Adolescents†

    0.5 to 1 mg/kg/dose (Max: 60 mg/dose) PO every 4 to 6 hours. Max: 7 mg/kg/day (Max: 300 mg/day), divided into 5 to 6 doses. Comparison of peak strength and activity 1 hour after a dose and immediately before the next dose facilitates individualized tailoring of dosage schedule. Response may diminish with time; a drug holiday may be beneficial.[34404] [64004] [64005] [64006] [64009]

    Neonates†

    0.5 to 1 mg/kg/dose PO every 4 to 6 hours. Max: 7 mg/kg/day, divided into 5 to 6 doses. Comparison of peak strength and activity 1 hour after a dose and immediately before the next dose facilitates individualized tailoring of dosage schedule. Response may diminish with time; a drug holiday may be beneficial.[34404] [64004] [64005] [64006]

    Oral dosage (extended-release tablets)

    The immediate effect of a 180 mg Timespan Tablet is about equal to that of a 60 mg regular-release tablet; however, duration of effectiveness, although varying in individual patients, averages 2.5 times that of a 60 mg dose.[32948]

    Adults

    180 to 540 mg PO 1 or 2 times daily. Adjust the dosage to the needs of the individual patient. For optimum control, it may be necessary to use the syrup or regular-release tablet form concurrently.[32948]

    Intravenous† or Intramuscular† dosage
    Adults

    One-thirtieth of the usual oral dose IV or IM.

    Infants, Children, and Adolescents

    0.05 to 0.15 mg/kg/dose IV or IM every 4 to 6 hours. Max: 10 mg/dose.[63307] To convert from oral doses, 1 mg of parenteral pyridostigmine is equivalent to 30 mg orally.[64007]

    Neonates

    0.05 to 0.15 mg/kg/dose IV or IM every 4 to 6 hours. To convert from oral doses, 1 mg of parenteral pyridostigmine is equivalent to 30 mg orally.

    For neuromuscular blockade reversal of non-depolarizing muscle relaxants.
    Intravenous dosage
    Adults

    0.1 to 0.25 mg/kg IV.

    Children† and Adolescents†

    0.1 to 0.25 mg/kg/dose IV.

    For adjunctive use in Soman nerve gas exposure prophylaxis.
    NOTE: For military medical use only. Pyridostigmine is for use in conjunction with protective garments.[64093]
    Oral dosage (regular-release tablets)
    Adults

    30 mg PO every 8 hours, starting at least several hours before exposure. Discontinue pyridostigmine at first sign of poisoning, and treat with atropine and pralidoxime immediately. The benefits and risks beyond 14 consecutive days of use have not been established; evaluate continued use in the context of likelihood of exposure.[64093]

    MAXIMUM DOSAGE

    Adults

    1,500 mg/day PO regular-release tablets or syrup or 1,080 mg/day PO extended-release tablets for myasthenia gravis; 180 mg/day PO regular-release tablets for Soman nerve gas exposure prophylaxis; 0.25 mg/kg/dose IV for neuromuscular blockade reversal.

    Geriatric

    1,500 mg/day PO regular-release tablets or syrup or 1,080 mg/day PO extended-release tablets for myasthenia gravis; 180 mg/day PO regular-release tablets for Soman nerve gas exposure prophylaxis; 0.25 mg/kg/dose IV for neuromuscular blockade reversal.

    Adolescents

    1 mg/kg/dose PO (Max: 60 mg/dose PO) and 7 mg/kg/day PO (Max: 300 mg/day PO) for myasthenia gravis.

    Children

    1 mg/kg/dose PO (Max: 60 mg/dose PO) and 7 mg/kg/day PO (Max: 300 mg/day PO) for myasthenia gravis.

    Infants

    1 mg/kg/dose PO and 7 mg/kg/day PO for myasthenia gravis.

    Neonates

    1 mg/kg/dose PO and 7 mg/kg/day PO for myasthenia gravis.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Lower doses may be required in patients with renal disease; base treatment on titration of drug dosage to effect.[32948] [64002]

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Regular-release tablets:
    Space doses to provide maximum relief when maximum strength is needed.
     
    Extended-release tablets:
    Swallow whole; do not crush or chew. Although the extended-release tablet is scored, breaking the tablet is not advised because no information is available (personal communication, Valeant Pharmaceuticals, July 2008).
    Space doses by at least 6 hours.
    For optimum control, it may be necessary to use pyridostigmine regular-release tablets or syrup concurrently.
    Some clinicians recommend using the extended-release product only at bedtime to treat weakness occurring at night or upon awakening.[23976] [32948]

    Oral Liquid Formulations

    Oral syrup or solution:
    This dosage form permits accurate dosage adjustment for children and brittle myasthenic patients who require fractions of 60 mg doses.
    It is more easily swallowed, especially in the morning, by patients with bulbar involvement.
    Administer using a calibrated measuring device. [64002]

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.[34253]

    Intravenous Administration

    Neuromuscular blockade reversal:
    The use of pyridostigmine injection for neuromuscular blockade reversal requires an experienced clinician familiar with the use of agents which reverse or antagonize neuromuscular blocking agents.
    Administer atropine (0.6 to 1.2 mg) or an equipotent dose of glycopyrrolate immediately before or simultaneously with pyridostigmine to minimize side effects, notably excessive secretions and bradycardia.
    Monitor muscle twitch response to peripheral nerve stimulation to obtain maximum clinical benefits and minimize possibility of overdosage.
    Satisfactory reversal can be evident by adequate voluntary respiration, respiratory measurements, and use of a peripheral nerve stimulator device. Ensure patient is well-ventilated and maintain a patent airway until complete recovery of normal respiration is assured.[34253]

    Intramuscular Administration

    Inject deeply into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel.

    STORAGE

    Generic:
    - Protect from moisture
    - Store and dispense in original container
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    Mestinon:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in a dry place
    Regonol :
    - Protect from light
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Pyridostigmine is contraindicated in patients with known hypersensitivity anticholinesterase agents.[34253]
     
    Pyridostigmine is for military medical use only as a pretreatment for the exposure to the chemical nerve agent Soman. Do not rely solely on the pretreatment with pyridostigmine and the antidotes, atropine and pralidoxime, to provide complete protection from poisoning by Soman. Primary protection against exposure to chemical nerve agents is the wearing of protective garments. Pyridostigmine alone will not protect against exposure to Soman; the efficacy of pyridostigmine is dependent upon the rapid use of atropine and pralidoxime after Soman exposure. Pyridostigmine must not be taken after exposure to Soman. If pyridostigmine is taken immediately before exposure (e.g., when the attack alarm is given) or at the same time as Soman poisoning, it is not expected to be effective and may exacerbate the effects of sublethal exposure to Soman.[64093]

    Bromide hypersensitivity

    Use pyridostigmine with caution in patients with known bromide hypersensitivity. Weigh the risks and benefits of pyridostigmine use against the potential for rash or other adverse reactions in these patients.[64093]

    Bladder obstruction, GI obstruction, ileus, urinary tract obstruction

    Pyridostigmine is contraindicated in mechanical intestinal obstruction (i.e., GI obstruction or ileus) or urinary tract obstruction (i.e., bladder obstruction).[32948] [34253] [64002]

    Cholinesterase inhibitor toxicity

    Myasthenic crisis may be difficult to distinguish from cholinergic crisis (i.e., cholinesterase inhibitor toxicity) on a symptomatic basis given both states are characterized by increasing or extreme muscle weakness. Differentiation is important since increases in pyridostigmine doses in cholinergic crisis or a refractory or "insensitive" state could have grave consequences; differential diagnosis of the 2 types of crisis may require edrophonium chloride use as well as clinical judgment. In managing the crises, myasthenic crisis suggests the need for more intensive anticholinesterase therapy while cholinergic crisis requires prompt withdrawal of all anticholinergic medications. The immediate use of atropine in cholinergic crisis is also recommended. Use atropine with caution for counteracting adverse effects. Atropine may be used to abolish or obtund gastrointestinal adverse effects or other muscarinic reactions, but by masking signs of cholinesterase inhibitor toxicity, can lead to inadvertent induction of cholinergic crisis.[32948] [64002]

    Asthma, bradycardia, cardiac arrhythmias, chronic obstructive pulmonary disease (COPD), glaucoma, hypertension

    Use pyridostigmine with caution in patients at increased risk of anticholinergic reactions, including patients with bronchial asthma, chronic obstructive pulmonary disease (COPD), bradycardia, or cardiac arrhythmias as well as patients being treated for hypertension or glaucoma with beta-adrenergic receptor blockers.[32948] [64002]

    Neonates

    Pyridostigmine injection contains benzyl alcohol as a preservative and is not for use in neonates. Exposure to excessive amounts of benzyl alcohol has been associated with hypotension, metabolic acidosis, and kernicterus in neonates. In this population, a "gasping syndrome" characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with dosages more than 99 mg/kg/day. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown, and premature and low-birth-weight neonates may be more likely to develop toxicity.[34253] [52949]

    Renal disease

    Lower pyridostigmine doses may be required in patients with renal disease; base treatment on titration of drug dosage to effect. Pyridostigmine is mainly excreted unchanged by the kidney.[32948] [64002]

    Adrenal insufficiency, electrolyte imbalance

    Electrolyte imbalance and diseases which lead to electrolyte imbalance, such as adrenal insufficiency, have been shown to alter neuromuscular blockade. Depending on the nature of the imbalance, either enhancement or inhibition may be expected. Consider the possibility that such circumstances may interfere with the restoration of neuromuscular function when using parenteral pyridostigmine for neuromuscular blockade reversal.[64093]

    Requires an experienced clinician

    The use of parenteral pyridostigmine for neuromuscular blockade reversal requires an experienced clinician familiar with the use of agents which reverse or antagonize the effects of neuromuscular blocking agents.[34253]

    Pregnancy

    There are no adequate data on the developmental risk associated with pyridostigmine use during human pregnancy.[63768] Guidelines consider oral pyridostigmine as the first-line treatment of myasthenia gravis during pregnancy. Intravenous pyridostigmine may produce uterine contractions, and its use is not recommended during pregnancy.[61823] Pyridostigmine crosses the placenta. There is a possibility that neonates born to myasthenic mothers can have transient muscle weakness if pyridostigmine is used during pregnancy.[63769]

    Breast-feeding

    Pyridostigmine is excreted in human milk.[49432] Previous American Academy of Pediatrics recommendations considered pyridostigmine to be generally compatible with breast-feeding.[27500] Based on the amount of pyridostigmine detected in breast milk of 2 nursing mothers, the estimated amount of pyridostigmine per kg of body weight of a nursing infant would be 0.1% or less of the maternal dose. Pyridostigmine milk concentrations ranged from 13 to 24 ng/mL at various times during dosing intervals on days 5 and 35 postpartum in a mother taking oral pyridostigmine 3 mg/kg per day (60 mg three times daily). Pyridostigmine concentrations ranged from the lower limit of detection (2 to 5 ng/mL) to 5 ng/mL during a dosage interval when the same mother received 2mg/kg per day (40 mg 3 times daily) at 102 days postpartum. In a second mother receiving 5 mg/kg per day (60 mg 5 times daily), pyridostigmine concentrations were 25 ng/mL at the time of a dose, and 22 ng/mL 2.5 hours after the dose at 60 days postpartum. No adverse effects occurred in the infants.[49432] Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for pyridostigmine and any potential adverse effects on the breast-fed infant from pyridostigmine or the underlying maternal condition.[63768]

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0-1.0

    Moderate

    hyperesthesia / Delayed / 2.0-2.0
    amblyopia / Delayed / 2.0-2.0
    fecal incontinence / Early / 0-1.0
    hallucinations / Early / Incidence not known
    hypertonia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    urinary incontinence / Early / Incidence not known
    depression / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known

    Mild

    abdominal pain / Early / 7.0-7.0
    diarrhea / Early / 7.0-7.0
    dysmenorrhea / Delayed / 3.0-3.0
    increased urinary frequency / Early / 2.0-2.0
    myalgia / Early / 2.0-2.0
    xerosis / Delayed / 2.0-2.0
    epistaxis / Delayed / 2.0-2.0
    pallor / Early / 0-1.0
    syncope / Early / 0-1.0
    ocular pain / Early / Incidence not known
    restlessness / Early / Incidence not known
    lacrimation / Early / Incidence not known
    headache / Early / Incidence not known
    agitation / Early / Incidence not known
    vertigo / Early / Incidence not known
    miosis / Early / Incidence not known
    bronchial secretions / Early / Incidence not known
    flatulence / Early / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    borborygmi / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    weakness / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    diaphoresis / Early / Incidence not known
    rash / Early / Incidence not known
    lethargy / Early / Incidence not known
    drowsiness / Early / Incidence not known

    DRUG INTERACTIONS

    Ambenonium Chloride: (Major) Other cholinesterase inhibitors can produce additive pharmacodynamic effects if used concomitantly with ambenonium chloride. Because ambenonium has a more prolonged action than other antimyasthenic drugs, simultaneous administration with other cholinergics is contraindicated except under strict medical supervision. The overlap in duration of action of several drugs complicates dosage schedules. Therefore, when a patient is to be given ambenonium, suspend the administration of all other cholinergics until the patient has been stabilized. In most instances, the myasthenic symptoms are effectively controlled by ambenonium use alone.
    Amifampridine: (Moderate) Coaministration of amifampridine and pyridostigmine may increase the risk for adverse reactions due to additive cholinergic effects. Monitor patients closely for new or worsening side effects such as headache, visual disturbances, watery eyes, excessive sweating, shortness of breath, nausea, vomiting, diarrhea, bradycardia, loss of bladder control, confusion, or tremors.
    Amikacin: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Aminoglycosides: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Amitriptyline: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Amitriptyline; Chlordiazepoxide: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Amoxapine: (Major) Amoxapine may antagonize some of the effects of parasympathomimetics. However, bethanechol has occasionally been used therapeutically to offset some of the adverse antimuscarinic effects of cyclic antidepressants. Due to their anticholinergic actions, some cyclic antidepressants, such as amoxapine, may potentially antagonize the therapeutic actions of pyridostigmine. Consider alternatives if concurrent therapy is needed.
    Articaine; Epinephrine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Atracurium: (Moderate) A higher atracurium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as pyridostigmine. Intravenous pyridostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as atracurium.
    Atropine: (Major) Coadministration of atropine and pyridostigmine bromide may produce a mutually antagonistic effect.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Coadministration of atropine and pyridostigmine bromide may produce a mutually antagonistic effect. (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of hyoscyamine.
    Atropine; Difenoxin: (Major) Coadministration of atropine and pyridostigmine bromide may produce a mutually antagonistic effect.
    Atropine; Diphenoxylate: (Major) Coadministration of atropine and pyridostigmine bromide may produce a mutually antagonistic effect.
    Atropine; Edrophonium: (Major) Coadministration of atropine and pyridostigmine bromide may produce a mutually antagonistic effect. (Major) Edrophonium and pyridostigmine are both parasympathomimetics. Coadministration results in additive effects and should be done cautiously.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Coadministration of atropine and pyridostigmine bromide may produce a mutually antagonistic effect. (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of hyoscyamine. (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of scopolamine.
    Azelastine; Fluticasone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Bacitracin: (Moderate) Parenteral administration of high doses of certain antibiotics such as bacitracin may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Beclomethasone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of hyoscyamine.
    Benztropine: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of benztropine. Benztropine might also antagonize some of the effects of the parasympathomimetics.
    Betamethasone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Budesonide: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Budesonide; Formoterol: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy. (Minor) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
    Bupivacaine Liposomal: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Bupivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Bupivacaine; Lidocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary. (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Bupivacaine; Meloxicam: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Chloroprocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Cholinergic agonists: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
    Ciclesonide: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Cisatracurium: (Moderate) A higher cisatracurium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as pyridostigmine. Intravenous pyridostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as cisatracurium.
    Clomipramine: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Cocaine: (Major) cholinesterase inhibitors reduce the metabolism of cocaine, therefore, prolonging cocaine's effects or increasing the risk of toxicity. It should be taken into consideration that the cholinesterase inhibition caused by echothiophate, demecarium, or isoflurophate may persist for weeks or months after the medication has been discontinued. Additionally, local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Dosage adjustment of the cholinesterase inhibitor may be necessary to control the symptoms of myasthenia gravis.
    Colistimethate, Colistin, Polymyxin E: (Moderate) Parenteral administration of high doses of certain antibiotics such as colistimethate sodium may intensify or produce neuromuscular blockade through their own pharmacologic actions. If unexpected prolongation of neuromuscular blockade or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect. Neuromuscular blockade may be associated with colistimethate sodium, and is more likely to occur in patients with renal dysfunction.
    Corticosteroids: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Cortisone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Deflazacort: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Demeclocycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Desipramine: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Dexamethasone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Dextromethorphan; Quinidine: (Moderate) Quinidine can potentiate the effects of depolarizing and nondepolarizing neuromuscular blockers. Recurrent paralysis may occur if quinidine injection is administered during recovery from use of nondepolarizing muscle relaxants. Consider the possible effect from quinidine when administering anticholinesterase agents such as pyridostigmine to antagonize neuromuscular blockade induced by nondepolarizing muscle relaxants
    Dicyclomine: (Major) The muscarinic actions of pyridoostigmine can antagonize the antimuscarinic actions of dicyclomine and vice-versa.
    Digoxin: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as digoxin. In one study involving multiple doses of galantamine at 24 mg/day with digoxin at a dose of 0.375 mg/day, there was no effect on the pharmacokinetics of digoxin, except one healthy subject was hospitalized due to second and third degree heart block and bradycardia.
    Disopyramide: (Moderate) Disopyramide possesses anticholinergic properties. Disopyramide should not be used in patients with myasthenia gravis because the anticholinergic properties of the drug could precipitate a myasthenic crisis. It is unclear if disopyramide can interfere with the cholinomimetic activity of pyridostigmine.
    Doxepin: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Doxycycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Edrophonium: (Major) Edrophonium and pyridostigmine are both parasympathomimetics. Coadministration results in additive effects and should be done cautiously.
    Etomidate: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Fludrocortisone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Flunisolide: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Fluticasone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Formoterol; Mometasone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Fospropofol: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Gentamicin: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Glycopyrrolate: (Minor) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
    Glycopyrrolate; Formoterol: (Minor) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
    Halogenated Anesthetics: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Magnesium salts may enhance the neuromuscular blockade and may interfere with the restoration of neuromuscular function. Consider the possibility of enhanced neuromuscular blockade from magnesium salts during pyridostigmine administration.
    Homatropine; Hydrocodone: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of homatropine.
    Hydrocortisone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Hyoscyamine: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of hyoscyamine.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of hyoscyamine.
    Imipramine: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Indacaterol; Glycopyrrolate: (Minor) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
    Kanamycin: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Ketamine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Levobupivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Lidocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Lidocaine; Prilocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary. (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Magnesium Salts: (Moderate) Magnesium salts may enhance the neuromuscular blockade and may interfere with the restoration of neuromuscular function. Consider the possibility of enhanced neuromuscular blockade from magnesium salts during pyridostigmine administration.
    Magnesium: (Moderate) Magnesium salts may enhance the neuromuscular blockade and may interfere with the restoration of neuromuscular function. Consider the possibility of enhanced neuromuscular blockade from magnesium salts during pyridostigmine administration.
    Maprotiline: (Major) Maprotiline may antagonize some of the effects of pyridostigmine.
    Mecamylamine: (Major) Ganglion-blockers, such as mecamylamine, can antagonize the effects of pyridostigmine. In addition, pyridostigmine might reduce the antihypertensive properties of these agents.
    Mepivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Mepivacaine; Levonordefrin: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of hyoscyamine.
    Methocarbamol: (Moderate) Methocarbamol may inhibit the effect of cholinesterase inhibitors. Methocarbamol also has sedative properties that may interfere with cognition. Therefore, methocarbamol should be used with caution in patients receiving cholinesterase inhibitors.
    Methscopolamine: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of methscopolamine.
    Methylprednisolone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Minocycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Mivacurium: (Moderate) A higher mivacurium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as pyridostigmine. Intravenous pyridostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as mivacurium.
    Mometasone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Neostigmine: (Major) Neostigmine and pyridostigmine are both parasympathomimetics. Coadministration results in additive effects and should be done cautiously.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Nortriptyline: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Omadacycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Oxybutynin: (Moderate) Oxybutynin is an antimuscarinic; the muscarinic actions of pyridostigmine could be antagonized when used concomitantly with oxybutynin.
    Pancuronium: (Moderate) A higher pancuronium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as pyridostigmine. Intravenous pyridostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as pancuronium.
    Paromomycin: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Physostigmine: (Major) Pyridostigmine and physostigmine are both parasympathomimetics. Coadministration results in additive effects and should be done cautiously.
    Plazomicin: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Polymyxin B: (Moderate) Parenteral administration of high systemic doses of certain antibiotics, such as Polymyxin B, may intensify or produce neuromuscular block or paralysis through its pharmacologic actions. If Polymyxin B or other newly introduced antibiotics are used in conjunction with nondepolarizing neuromuscular blocking drugs during surgery, unexpected prolongation of neuromuscular block or resistance to its reversal should be considered a possibility.
    Polymyxins: (Moderate) Parenteral administration of high doses of certain antibiotics such as colistimethate sodium may intensify or produce neuromuscular blockade through their own pharmacologic actions. If unexpected prolongation of neuromuscular blockade or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect. Neuromuscular blockade may be associated with colistimethate sodium, and is more likely to occur in patients with renal dysfunction.
    Prednisolone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Prednisone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Prilocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Prilocaine; Epinephrine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Procainamide: (Major) Procainamide may antagonize the effects of cholinesterase inhibitors such as pyridostigmine in the treatment of myasthenia gravis. Isolated case reports describe worsening symptoms shortly after procainamide is added however, this interaction may be due more to procainamide's local anesthetic properties than its anticholinergic properties.
    Procaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Propantheline: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of propantheline.
    Propofol: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Protriptyline: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Quinidine: (Moderate) Quinidine can potentiate the effects of depolarizing and nondepolarizing neuromuscular blockers. Recurrent paralysis may occur if quinidine injection is administered during recovery from use of nondepolarizing muscle relaxants. Consider the possible effect from quinidine when administering anticholinesterase agents such as pyridostigmine to antagonize neuromuscular blockade induced by nondepolarizing muscle relaxants
    Quinine: (Major) The actions of quinine on skeletal muscle are pharmacologically opposite to those of cholinesterase inhibitors. Therefore, quinine may interfere with the actions of cholinesterase inhibitors in treating such conditions as myasthenia gravis. This represents a pharmacodynamic interaction with cholinesterase inhibitors rather than a pharmacokinetic interaction.
    Rocuronium: (Moderate) A higher rocuronium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as pyridostigmine. Intravenous pyridostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as rocuronium.
    Sarecycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Scopolamine: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of scopolamine.
    Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Magnesium salts may enhance the neuromuscular blockade and may interfere with the restoration of neuromuscular function. Consider the possibility of enhanced neuromuscular blockade from magnesium salts during pyridostigmine administration.
    Streptomycin: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Succinylcholine: (Moderate) Pyridostigmine does not antagonize, and may prolong, the Phase I block of succinylcholine. If given before succinylcholine is metabolized by cholinesterase, pyridostigmine may prolong rather than shorten paralysis. Depending on the dose and duration of succinylcholine administration, the characteristic depolarizing neuromuscular block (Phase I block) may change to a block with characteristics superficially resembling a non-depolarizing block (Phase II block). When this diagnosis is confirmed with a peripheral nerve stimulator, it may sometimes be reversed with anticholinesterase drugs, such as pyridostigmine. Anticholinesterase drugs may not always be effective.
    Tetracaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Tetracycline: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Tetracyclines: (Moderate) Parenteral administration of high doses of certain antibiotics such as tetracyclines may intensify or produce neuromuscular block through their own pharmacologic actions. If unexpected prolongation of neuromuscular block or resistance to its reversal with pyridostigmine occurs, consider the possibility of an antibiotic effect.
    Tobramycin: (Moderate) Aminoglycosides have been associated with neuromuscular blockade when used as an abdominal irrigant intraoperatively. Although the risk of neuromuscular blockade is remote with parenteral aminoglycoside therapy, these antibiotics should be used cautiously in myasthenic patients. This represents a pharmacodynamic interaction with cholinesterase inhibitors when used to treat myasthenia gravis, rather than a pharmacokinetic interaction.
    Triamcinolone: (Moderate) Concomitant use of anticholinesterase agents. such as pyridostigmine, and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.
    Tricyclic antidepressants: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Trihexyphenidyl: (Major) The muscarinic actions of pyridostigmine can antagonize the antimuscarinic actions of trihexyphenidyl.
    Trimipramine: (Moderate) Tricyclic antidepressants may antagonize some of the effects of parasympathomimetics, such as pyridostigmine, due to their anticholinergic activity.
    Vecuronium: (Moderate) A higher vecuronium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as pyridostigmine. Intravenous pyridostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as vecuronium.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate data on the developmental risk associated with pyridostigmine use during human pregnancy.[63768] Guidelines consider oral pyridostigmine as the first-line treatment of myasthenia gravis during pregnancy. Intravenous pyridostigmine may produce uterine contractions, and its use is not recommended during pregnancy.[61823] Pyridostigmine crosses the placenta. There is a possibility that neonates born to myasthenic mothers can have transient muscle weakness if pyridostigmine is used during pregnancy.[63769]

    Pyridostigmine is excreted in human milk.[49432] Previous American Academy of Pediatrics recommendations considered pyridostigmine to be generally compatible with breast-feeding.[27500] Based on the amount of pyridostigmine detected in breast milk of 2 nursing mothers, the estimated amount of pyridostigmine per kg of body weight of a nursing infant would be 0.1% or less of the maternal dose. Pyridostigmine milk concentrations ranged from 13 to 24 ng/mL at various times during dosing intervals on days 5 and 35 postpartum in a mother taking oral pyridostigmine 3 mg/kg per day (60 mg three times daily). Pyridostigmine concentrations ranged from the lower limit of detection (2 to 5 ng/mL) to 5 ng/mL during a dosage interval when the same mother received 2mg/kg per day (40 mg 3 times daily) at 102 days postpartum. In a second mother receiving 5 mg/kg per day (60 mg 5 times daily), pyridostigmine concentrations were 25 ng/mL at the time of a dose, and 22 ng/mL 2.5 hours after the dose at 60 days postpartum. No adverse effects occurred in the infants.[49432] Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for pyridostigmine and any potential adverse effects on the breast-fed infant from pyridostigmine or the underlying maternal condition.[63768]

    MECHANISM OF ACTION

    Pyridostigmine is a reversible cholinesterase inhibitor, preventing the destruction of acetylcholine by cholinesterase and thereby allowing freer transmission of nerve impulses across the neuromuscular junction. Pyridostigmine may produce depolarization block when administered at doses above the recommended therapeutic range. The therapeutic index of parenteral pyridostigmine (ratio of reversal dose to blocking dose) is approximately 1:6. The antagonism of neuromuscular blockade by anticholinesterase agents may be influenced by the degree of spontaneous recovery achieved when the reversal agent is administered, by the particular relaxant administered, acid-base balance, body temperature, electrolyte imbalance, and concomitant medications. The effect of pyridostigmine in Soman-induced toxicity is presumed to result from its reversible inhibition of a critical number of acetylcholinesterase active sites in the peripheral nervous system, protecting them from irreversible inhibition by Soman. Pyridostigmine is not thought to enter the brain in significant amounts. When the pyridostigmine-induced inhibition of the enzyme is subsequently reversed, there is a small residual amount of enzyme activity that is adequate to sustain life provided atropine and pralidoxime are administered.[32948] [34253] [64093]

    PHARMACOKINETICS

    Pyridostigmine is administered orally and intravenously. The pyridostigmine volume of distribution is about 19 +/- 12 L, indicating that it distributes into tissues. Pyridostigmine undergoes hydrolysis by cholinesterases and is metabolized in the liver. It is excreted in the urine both as unchanged drug and its metabolites. The systemic clearance of pyridostigmine is 830 mL/minute, and the elimination half-life is approximately 3 hours. Pyridostigmine is a quaternary ammonium compound and does not readily cross the blood-brain barrier.[64093]
     
    Affected cytochrome P450 isoenzymes and/or drug transporters: none

    Oral Route

    Pyridostigmine is poorly absorbed from the gastrointestinal tract with an absolute bioavailability of 10% to 20%. The pharmacokinetics of pyridostigmine are linear over the dose range of 30 to 60 mg. After a single oral dose of pyridostigmine 30 mg in the fasting state, the Tmax was 2.2 +/- 1 hours. After multiple doses of pyridostigmine (30 mg every 8 hours for 21 days), the average steady-state pyridostigmine trough concentration was about one-fourth of the peak concentration after a single dose.[64093]

    Intravenous Route

    After intravenous administration, the onset time to peak effect is dose-dependent. Return of twitch height to 90% of control occurs within 6 minutes after pyridostigmine 0.25 mg/kg IV. At lower doses, full recovery usually occurs within 15 minutes for most patients, although others may require 30 minutes or more. The therapeutic index of parenteral pyridostigmine (ratio of reversal dose to blocking dose) is approximately 1:6.[34253]