Neostigmine Methylsulfate (neostigmine methylsulfate)

No dosing information is available for this tab.

Neostigmine methylsulfate is administered by slow IV injection (over a period of at least 1 minute). The drug also has been administered by IM or subcutaneous injection+, but the manufacturer of the currently available injectable preparation labeled for reversal of neuromuscular blocking agents states that the injection is for IV use only.

Neostigmine methylsulfate injection should be stored at controlled room temperature (20-25degreesC) but may be exposed to temperatures ranging from 15-30degreesC; the injection should be stored in the original carton until time of use and protected from light.

No dosing information is available for this tab.

No dosing information is available for this tab.

Drug interaction studies have not been conducted to date with neostigmine methylsulfate. Clinically important drug interactions are not likely to occur if neuromuscular monitoring is employed and both relaxants and reversal agents are titrated to effect.

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.

*Known hypersensitivity to neostigmine.

*Mechanical obstruction of the intestinal or urinary tract.

*Peritonitis.

• Colonic necrosis
• Mechanical intestinal obstruction
• Peritonitis
• Urinary tract obstructive uropathy

• Hypotension
• Sinus bradycardia

• Asthma
• Cardiac arrhythmia
• Coronary artery disease
• Hyperthyroidism
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Parkinsonism
• Peptic ulcer
• Seizure disorder

The most common adverse effects of neostigmine include bradycardia, nausea, and vomiting. Adverse effects of neostigmine methylsulfate generally are due to exaggerated pharmacologic effects of the drug, particularly at muscarinic-cholinergic receptors.

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

No enhanced messaging available.

Neostigmine may be used in pediatric patients of all ages to reverse the effects of nondepolarizing neuromuscular blocking agents after surgery. The available data indicate that efficacy and pharmacokinetics of neostigmine are similar across all pediatric age groups and also similar to those in adults when the same dosing guidelines are applied.

Based on limited data, neostigmine dosing requirements for reversal of neuromuscular blockade may be lower in infants and neonates than in older pediatric patients and adults; however, pediatric patients have a greater risk of incomplete reversal of neuromuscular blockade because of their decreased respiratory reserve. Therefore, the risks of administering higher doses of neostigmine (up to maximum recommended dosage) should not outweigh the risks associated with incomplete reversal in this age group.

Because pediatric patients, particularly neonates and infants, may be more sensitive to changes in heart rate, the effects of anticholinergic agents should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension.

It is not known whether neostigmine can cause fetal harm when administered to pregnant women or affect reproductive capacity; the drug should be used during pregnancy only when clearly indicated as no adequate or well-controlled studies of the drug have been conducted in pregnant women. Administration of anticholinesterase drugs such as neostigmine to pregnant women near term may cause uterine irritability and induce premature labor.

There are limited data from animal reproduction studies; in such studies, no teratogenic or other adverse effects were identified; however, drug exposure was well below the predicted exposures in humans.

It is not known whether neostigmine is distributed into human milk. Caution should be exercised when the drug is used in nursing women.

Although dosage adjustments are not required in geriatric patients undergoing reversal of neuromuscular blockade, a longer period of monitoring is recommended in such patients to ensure that additional doses of neostigmine are not necessary to adequately reverse neuromuscular blockade.

Because geriatric patients may have decreased renal function, neostigmine should be used with caution and increased monitoring in this age group. The duration of action of neostigmine is prolonged in geriatric patients; however, such patients also experience slower spontaneous recovery from neuromuscular blocking agents. Geriatric patients should be monitored for longer periods of time to ensure that additional doses of neostigmine are not necessary to adequately reverse neuromuscular blockade.