Regonol (pyridostigmine bromide)

Since pyridostigmine is excreted predominantly by the kidneys, the manufacturer of Mestinon(R) states that lower dosages of pyridostigmine bromide may be required in patients with renal disease. In such patients, the dosage should be titrated carefully to produce the desired effect.

Pyridostigmine bromide is administered orally (as conventional tablets, extended-release tablets, or oral solution) or by IV injection. The drug also has been administered by IM injection, but the manufacturer of the currently available injectable preparation states that the injection is for IV use only.

When used as a neuromuscular reversal agent, pyridostigmine should be administered only by trained clinicians experienced in the use of such agents. Patients must be well ventilated and have a patent airway prior to administration of pyridostigmine and until complete recovery of normal respiration. Continuous monitoring of neuromuscular function is recommended to ensure adequate reversal from the neuromuscular block. To exclude with certainty the possibility of residual paralysis, an objective (quantitative) method of monitoring such as peripheral nerve stimulation should be used in conjunction with other clinical assessments (e.g., observation of skeletal muscle tone, respiratory measurements). Adequate recovery of neuromuscular function generally is defined as a train-of-four (TOF) ratio of 0.9 in addition to the patient's ability to maintain satisfactory ventilation and a patent airway.

When pyridostigmine is administered as conventional dosage forms for the symptomatic treatment of myasthenia gravis, the dosage should be adjusted so that larger doses are taken at times of greatest fatigue (e.g., 30-45 minutes before meals to assist patients who have difficulty eating).

Pyridostigmine oral solution is especially useful for children and patients who have difficulty swallowing, and the solution may be administered through a nasogastric tube, if necessary.

No dosing information is available for this tab.

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There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Selected Anticholinesterase/Corticosteroids

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of this interaction is unknown.

CLINICAL EFFECTS: Concurrent use of these agents may contribute to increased muscle weakness and decreased response to anticholinesterases shortly after onset of corticosteroid therapy in the treatment of myasthenia gravis. Deterioration in muscle strength, including severe muscular depression, has been documented in patients with myasthenia gravis while receiving corticosteroids and anticholinesterases.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, hold anticholinesterase agents at least 24 hours before initiating corticosteroid therapy. If concurrent use is necessary, close observation of the patient is indicated and life support systems should be available.

DISCUSSION: Decreased effectiveness of anticholinesterases during the period of corticosteroid-induced increased weakness probably reflects a temporary increase in the severity of the disease process itself rather than a specific, direct interaction between the two drugs. Despite the initial adverse effect, glucocorticoid (or ACTH) therapy subsequently produces improvement, beyond pre-therapy muscle strength, in most myasthenia gravis patients. In an uncontrolled study involving nine patients receiving therapeutic doses of pyridostigmine, the concurrent administration of methylprednisolone resulted in a decrease in muscle strength in 71% of treatment courses. During 57% of treatment courses, severe muscle weakness occurred, necessitating mechanical ventilation. Improvement in muscle strength and response to pyridostigmine above baseline levels occurred after methylprednisolone was discontinued. Other clinical observations have indicated that the concomitant use of these agents can affect muscle strength, although each agent alone has been used successfully in treating myasthenia gravis.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Anticholinesterases/Beta-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases and increase cholinergic activity. Use of anticholinesterases may have vagotonic effects on heart rate (e.g. bradycardia). Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

CLINICAL EFFECTS: Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of anticholinesterases and beta-blockers is not recommended. Additive effects may be increased with cardioselective beta-blockers (e.g. atenolol). Monitor patients closely if concurrent use is warranted.(1)

DISCUSSION: Concurrent use of anticholinesterases and beta-blockers may have additive effects on cardiac conduction and increase the risk of bradycardia.(1) A case report of a 65 year old African American female had a witnessed a presyncopal episode followed by a true syncopal episode with concurrent use of rivastigmine and atenolol. On day 2 of the hospital stay, the patient developed bradycardia with a heart rate in the 40s and sinus pauses greater than 2 seconds. Atenolol was discontinued yet bradycardia persisted. Following discontinuation of rivastigmine, sinus pauses resolved and heart rate returned to normal.(2) A population-based cohort study in Ontario, Canada reviewed the relationship between cholinesterase inhibitor use and syncope-related outcomes over a two year period. Hospital visits for syncope were more frequent in patients receiving cholinesterase inhibitors than controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.57-1.98). Other syncope-related events were also more common in patients receiving cholinesterase inhibitors than controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR 1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(3) A population based case-time-control study of 1,009 patients hospitalized for bradycardia within 9 months of using a cholinesterase inhibitor were reviewed for outcomes. Of these patients, 11% required pacemaker insertion during hospitalization and 4% died prior to discharge. With adjustment for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor drug (adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51). Risk was similar in patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34; 95% CI 1.16-4.71).(4)

Anticholinesterases/Succinylcholine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases, delaying succinylcholine hydrolysis and prolonging its duration of action.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects of succinylcholine, producing profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of anticholinesterases and succinylcholine in patients with depolarizing type (phase I) neuromuscular blockade. In addition, use with caution in the presence of a nondepolarizing type (phase II) blockade. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concomitant administration of anticholinesterases and succinylcholine has been associated with prolonged respiratory depression and apnea.

Cholinergics/Quinidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The anticholinergic properties of quinidine may oppose cholinergic drug effects.

CLINICAL EFFECTS: Quinidine may antagonize the effects of cholinergic drugs in the treatment of myasthenia gravis. Cardiac slowing secondary to cholinergic drugs would tend to be prevented by quinidine.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If both drugs are administered, observe the myasthenic patient for signs and symptoms of the disease.

DISCUSSION: Caution is warranted in co-administration of these drugs due to their opposing pharmacologic properties.

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• Gastrointestinal obstruction
• Urinary tract obstructive uropathy

There are no severe contraindications for this drug.

• Asthma
• Bradycardia
• Chronic obstructive pulmonary disease
• Kidney disease with reduction in glomerular filtration rate (GFr)

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Rare or Very Rare

• Bradycardia
• Cardiac arrhythmia
• Hypotension

More Frequent

• Abdominal pain with cramps
• Diarrhea
• Hyperhidrosis
• Nausea
• Sialorrhea
• Vomiting

Less Frequent

• Abdominal distension
• Acute cognitive impairment
• Alopecia
• Dizziness
• Dry skin
• Dysmenorrhea
• Dyspnea
• Epistaxis
• Eye tearing
• Flatulence
• Hypertonia
• Hypoesthesia
• Increased bronchial secretions
• Increased urinary frequency
• Miosis
• Myalgia
• Neck pain
• Ocular pain
• Rhinorrhea
• Tingling sensation of hands or feet
• Toxic amblyopia
• Urinary urgency

Rare or Very Rare

• Cramps
• General weakness
• Headache disorder
• Malaise
• Muscle fasciculation
• Skin rash
• Vertigo

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Few data are available regarding the effects of cholinesterase inhibitors, including pyridostigmine, on the fetus because of the rarity of maternal conditions requiring the use of these drugs during pregnancy. Transient muscular weakness has occurred in 10-20% of neonates whose mothers received anticholinesterase drugs for the treatment of myasthenia gravis, although similar symptoms have also been reported in infants whose mothers were not treated with these drugs. Some experts state that oral pyridostigmine is the first-line treatment of choice for pregnant women with myasthenia gravis. However, anticholinesterase drugs may cause uterine irritability and induce premature labor when given IV to pregnant women near term. Use of pyridostigmine in pregnant women requires that the possible benefits be weighed against the potential risks.

Since it is not known whether pyridostigmine is distributed into milk, the drug should be used with caution in nursing women.

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