Neostigmine is an oral and parenteral parasympathomimetic agent (cholinesterase inhibitor). It is similar to, but shorter-acting than, pyridostigmine. Neostigmine bromide is the oral form of the drug, while neostigmine methylsulfate is the intravenous (IV), intramuscular (IM), and subcutaneous (SC) form. Both formulations (bromide and methylsulfate) are approved for the symptomatic treatment of myasthenia gravis when given via oral, SC, and IM routes. Neostigmine methylsulfate is also indicated for reversal of the effects of non-depolarizing neuromuscular blocking agents when given IV and for the prevention and treatment of post-operative distention and urinary retention (after exclusion of a mechanical obstruction) when given as an IM or SC injection. Neostigmine was approved by the FDA in 1939.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine. Both conditions result in extreme muscle weakness but require different treatment strategies. Myasthenic crisis requires treatment with anticholinesterase therapy. In contrast, cholinergic crisis (indicative of anticholinesterase overdose) requires discontinuation of cholinesterase inhibitor therapy.
Route-Specific Administration
Oral Administration
-Dosage should be adjusted for each individual patient as needed; divide daily dosage and give larger portions at times of greatest fatigue (e.g., afternoon, mealtimes).
-In order to determine the optimal therapeutic regimen, patients should be encouraged to keep a daily record of his or her condition.
Injectable Administration
-Parenteral doses of neostigmine methylsulfate are not equivalent to oral doses of neostigmine bromide. As a general rule, 15 mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigmine methylsulfate parenterally, due to poor absorption of the tablet from the intestinal tract.
-An anticholinergic agent (e.g., atropine or glycopyrrolate) should be administered prior to or concurrently with (via a separate syringe) neostigmine.
-Resuscitation equipment should always be available when giving neostigmine parenterally.
-During administration, frequently monitor pulse, respiratory rate, blood pressure, and neurologic status.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-The IV dose should only be administered by a trained healthcare professional familiar with neuromuscular blocking agents.
-In order to effectively administer IV neostigmine, use of a peripheral nerve stimulator capable of delivering a train-of-four (TOF) stimulation is recommended.
-Inject via slow IV push over at least 1 minute.
-The patient should be well ventilated and a patent airway maintained until complete recovery of normal ventilation is achieved. Closely monitor the patient until satisfactory recovery of the patient's respiratory status has been achieved, as determined by skeletal muscle tone, respiratory movements, and response to peripheral nerve stimulation.
Intramuscular Administration
-Inject deeply into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel.
Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.
Neostigmine has been associated with digestive/gastrointestinal (GI) adverse events, with hypersalivation being the most common. During clinical trials involving 200 adults exposed to IV neostigmine methylsulfate, >= 1% experienced nausea, and vomiting. Xerostomia was also reported by >= 1% of patients who received IV neostigmine methylsulfate in clinical trials; however, it is unclear whether the patients also received an anticholinergic agent at the time of administration. Other GI events reported during the post-marketing use of neostigmine include abdominal pain or bowel cramps, diarrhea, flatulence, and increased peristalsis. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Miosis, visual impairment, and excessive lacrimation may occur with neostigmine use, which are extension of the drug's pharmaceutical effects.
During clinical trials involving 200 adults exposed to neostigmine methylsulfate, >= 1% experienced prolonged neuromuscular blockage, post-operative shivering, dizziness, insomnia, and headache. Other neurologic adverse reactions reported during the post-marketing period include convulsions or seizures, loss of consciousness (coma), drowsiness, and dysarthria. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials involving 200 adults exposed to neostigmine methylsulfate, >= 1% developed bradycardia, hypotension, and sinus tachycardia. Other cardiovascular adverse events reported during the post-marketing period include arrhythmia exacerbation (e.g., AV block, nodal rhythm), nonspecific EKG changes, syncope, and cardiac arrest. Cardiovascular reactions are predominately noted during the use of parenteral neostigmine. The concurrent administration of an IV anticholinergic drug (e.g., atropine or glycopyrrolate) is recommended to minimize the risk of cardiovascular complications associated with IV neostigmine and large SC/IM neostigmine doses.
Dyspnea and oxygen desaturation (< 90%) were observed in >= 1% of the 200 adults exposed to neostigmine methylsulfate during clinical trials. Other respiratory adverse events reported during the post-marketing period include respiratory depression, respiratory arrest, and bronchospasm. Increased oral, pharyngeal, and bronchial secretions, resulting from the cholinergic effects of neostigmine, have also been reported.
Muscle fasciculation is a frequently reported adverse reaction to neostigmine treatment. Other musculoskeletal adverse events reported during the post-marketing period include muscle cramps and spasms, myasthenia, arthralgia, and weakness. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Pruritus was reported by >= 1% of adults receiving treatment with neostigmine methylsulfate during clinical trials. Known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, rash (unspecified), facial swelling, peripheral edema, fever, flushing, hypotension, bronchospasm, anaphylaxis, and bradycardia. In addition, adverse reactions such as rash, urticaria, pruritus, flushing, and diaphoresis have been independently reported.
The cholinergic effects of neostigmine may lead to increased urinary frequency.
General adverse reactions observed in >= 1% of adults exposed to neostigmine methylsulfate during clinical trials included incisional complications, procedural pain/complications, and pharyngolaryngeal pain. Neostigmine has also been associated with diaphoresis and flushing during the post-marketing period. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Anticholinesterase drugs, including neostigmine, may cause uterine irritability and induce premature labor when administered intravenously to pregnant women near term.
Neostigmine is contraindicated in patients with known hypersensitivity to the drug. Because of the presence of the bromide ion, oral neostigmine bromide tablets are also contraindicated in patients with a known bromide hypersensitivity. Prior to neostigmine administration, ensure medications used for the treatment of anaphylactic reactions are readily available.
Neostigmine is contraindicated in patients with mechanical GI obstruction or urinary tract obstruction because it increases contractions of smooth muscle. Neostigmine can exacerbate peritonitis by increasing GI motility and its use in this condition is contraindicated. Neostigmine also stimulates gastric acid secretion and should be used with caution in peptic ulcer disease. Neostigmine should be used with caution in patients with vagotonia. Large doses of neostigmine should be avoided in situations where there might be an increased absorption rate from the intestinal tract. Neostigmine should be used with caution when co-administered with anticholinergic drugs, in order to avoid reduction of intestinal motility.
Overdosage of neostigmine can cause cholinesterase inhibitor toxicity (cholinergic crisis), which may be hard to differentiate from myasthenic crisis. It is important to differentiate between myasthenic crisis and cholinergic crisis since both conditions present with similar symptoms. Myasthenic crisis requires treatment with anticholinesterase therapy while cholinergic crisis (indicative of anticholinesterase overdose, with excess acetylcholine available through cholinesterase inhibition) requires discontinuation of cholinesterase inhibitor therapy.
Neostigmine must be used cautiously in patients with hypotension and bradycardia because it can further decrease the blood pressure and heart rate by increasing vagal tone. Neostigmine also has direct stimulatory effects on the myocardium, which can lead to dysrhythmias and increased oxygen demand. These effects may be dangerous for patients with cardiac disease, particularly coronary artery disease and/or cardiac arrhythmias. In addition, although neostigmine is used for the management of myasthenia gravis, these patients are at increased risk of cardiovascular complications. To reduce the risk for cardiovascular complications, administer an IV anticholinergic agents (e.g., atropine or glycopyrrolate) before giving neostigmine.
Neostigmine should be used cautiously in patients with hyperthyroidism or seizure disorder because it can exacerbate these conditions by stimulating the CNS.
Neostigmine can cause bronchospasms and increased bronchial secretions; therefore, caution is advised when administering to patients with acute bronchospasm or asthma.
Neostigmine is metabolized by microsomal liver enzymes and hydrolyzed by cholinesterases. Theoretically, hepatic disease associated with significant hepatic impairment could hinder metabolism, although the clinical significance of this effect is not known. Initiate dosage cautiously; monitor for potential drug toxicity.
After neostigmine administration, about 50-67% of a dose is excreted in the urine as unchanged drug, and the drug half-life is prolonged in patients with end-stage renal disease. Significant renal impairment or renal failure may lead to accumulation of neostigmine. Although no dose adjustments are recommended in the FDA-approved product labels, close monitoring is advised.
Use caution when administering neostigmine to geriatric patients. Elderly patients are more likely to have decreased renal function, and the duration of action is prolonged in the elderly. However, geriatric patients also experience slower recovery from neuromuscular blocking agents; therefore, dosage adjustments are usually not needed. Monitor geriatric patients for longer periods of time than younger patients to ensure additional doses are not needed. The duration of monitoring should be predicated on the anticipated duration of action for the neuromuscular blocking agent used on the patient.
Use neostigmine during pregnancy only if clearly needed. There are no adequate or well-controlled studies of the use of neostigmine in pregnant women. It is not known if neostigmine can cause fetal harm or affect reproductive ability when administered during pregnancy. No adverse effects or teratogenic effects were seen in animal studies in which rats or rabbits were treated with neostigmine during organogenesis, although doses utilized were well below predicted exposures in humans. The effect of neostigmine on the mother and fetus, with regard to labor and delivery, including need for intervention during delivery (e.g., forceps or resuscitation of the newborn), is not known. Anticholinesterase drugs, including neostigmine, may cause uterine irritability and induce premature labor when administered to pregnant women near term.
Consider the developmental and health benefits of breast-feeding along with the mother's need for neostigmine and any potential adverse effects on the breast-fed child from neostigmine or the underlying maternal condition. Neostigmine has not been studied in lactating women. It is not known whether neostigmine is present in human milk, or if neostigmine has effects on milk production or the breast-fed child.
As a general rule, 15 mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigmine methylsulfate parenterally, due to poor absorption of the tablet from the intestinal tract.
For the symptomatic treatment of myasthenia gravis:
NOTE: It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine. Both conditions result in extreme muscle weakness but require different treatment strategies.
Oral dosage:
Adults: Initially, 15 mg PO 3 times per day. The daily dosage should be gradually increased at intervals of 1 or more days. The usual maintenance dosage is 15 to 375 mg/day (average 150 mg) PO, given in divided doses. Some patients require 30 to 40 mg PO every 2 to 4 hours.
Infants*, Children*, and Adolescents*: 2 mg/kg/day PO divided every 3 to 4 hours. Maximum: 375 mg/day. The average adult dose is 150 mg/day. Dosage and schedule should be adjusted for each individual patient as needed; larger portions of daily divided dose should be given at times of greatest fatigue.
Neonates*: Initially, 0.5 to 1 mg PO at least 30 minutes prior to each feeding. Increase dose gradually until sucking and swallowing are sufficient for adequate nutritional intake. Slowly taper off as symptoms remit. Neonates with transient maternally transmitted myasthenia gravis may require cholinesterase inhibitors for a period of days to weeks.
Intramuscular or Subcutaneous dosage:
NOTE: Large parenteral doses should be accompanied by IV atropine to counteract the adverse muscarinic effects of neostigmine.
Adults: 0.5 mg IM or subcutaneously. Base subsequent doses on patient's response to therapy.
Infants*, Children*, and Adolescents*: 0.01 to 0.04 mg/kg/dose IM or subcutaneously every 2 to 4 hours PRN. Dosage and schedule should be adjusted for each individual patient as needed. Transition to PO when appropriate. Large parenteral doses should be accompanied by IV atropine to counteract the adverse muscarinic effects (e.g., bradycardia, hypersalivation, hyperperistalsis) of neostigmine.
Neonates*: Initially, 0.05 to 0.1 mg IM or subcutaneously at least 20 minutes prior to each feeding. Increase dose gradually until sucking and swallowing are sufficient for adequate nutritional intake. Transition to PO dosage form and slowly taper off as symptoms remit. Neonates with transient maternally transmitted myasthenia gravis may require cholinesterase inhibitors for a period of days to weeks.
For myasthenia gravis diagnosis*:
NOTE: All anticholinesterase medications should be discontinued for at least 8 hours before administering neostigmine. Atropine should be administered IV immediately prior to or IM 30 minutes before neostigmine.
Intramuscular dosage:
Adults: 1.5 mg (0.022 mg/kg) IM, given as a single dose. If a cholinergic reaction occurs, the test should be discontinued and additional atropine should be administered. If the results are inconclusive, the patient can be tested on another day with 0.031 mg/kg IM as a single dose (preceded by atropine).
Neonates, Infants, Children, and Adolescents: 0.025 to 0.04 mg/kg IM given as a single dose. Maximum: 1.5 mg/dose. Peak effect seen in 20 to 40 minutes. If the result is ambiguous, another dose may be administered 4 hours after initial dose. IV access and electrocardiogram monitoring are recommended during test. Atropine should be readily available. All anticholinesterase medications should be discontinued for at least 8 hours before administering neostigmine. Atropine should be administered IV immediately prior to or IM 30 minutes before neostigmine.
For non-depolarizing neuromuscular blockade reversal:
NOTE: Administer an IV anticholinergic agent (e.g., atropine or glycopyrrolate) either prior to or concomitantly with (via separate syringes) neostigmine. For bradycardic patients, the anticholinergic agent should always be administered before neostigmine.
NOTE: Use of a peripheral nerve stimulator capable of delivering a train-of-four (TOF) stimulus is recommended to determine when to initiate neostigmine therapy and the need for additional doses.
NOTE: Ensure patient is adequately ventilated and maintains a patent airway until complete recovery of normal ventilation is achieved. Skeletal muscle tone, respiratory measurements, and response to peripheral nerve stimulation should be used to assess the patient's ventilation status. The time to full recovery depends on the patient's medical condition, as well as the pharmacokinetics of neostigmine and the neuromuscular blocking agent used.
Intravenous dosage (excluding Bloxiverz):
Adults: 0.5 to 2 mg slow IV injection. Repeat as required; the total dose rarely should exceed 5 mg.
Neonates, Infants, Children, and Adolescents: 0.03 to 0.05 mg/kg/dose IV in conjunction with atropine or glycopyrrolate. Dose required may be dependent on degree of neuromuscular block; effective doses in studies ranged from 0.01 to 0.07 mg/kg/dose. Maximum total dose: 5 mg. In a dose-response study of 27 patients (aged 3 weeks to 8 years), the neostigmine mg/kg dose required to produce 50% antagonism of tubocurarine-induced blockade was 30% to 40% less than for adults.
Intravenous dosage (Bloxiverz only):
Adults, Adolescents, Children, Infants, and Neonates: Initiate therapy with a 0.03 to 0.07 mg/kg/dose via slow IV injection (over at least 1 minute). The twitch response to the first TOF stimulus must be at least 10% of baseline prior to administration. Dose selection should be based on the extent of spontaneous recovery at time of injection, half-life of the neuromuscular blocking agent (NMBA) to be reversed, and need for rapid NMBA reversal. Use the 0.03 mg/kg dose for reversal of NMBAs with short half-lives, when the first twitch response to the TOF stimulus is substantially greater than 10% of baseline, or when a second twitch response is present. The 0.07 mg/kg dose is recommended for reversal of NMBAs with longer half-lives (e.g., vecuronium, pancuronium), when first twitch response is relatively weak, or if there is a need for rapid recovery. Recovery (TOF twitch ratio of 90%) is generally achieved within 10 to 20 minutes of administration. Additional doses may be required; the maximum total dose is 0.07 mg/kg or 5 mg, whichever is less. An anticholinergic agent (e.g., atropine or glycopyrrolate) should be administered prior to or in conjunction with neostigmine. Monitor response to nerve stimulation, muscle tone, and respiratory status; maintain assisted ventilation until complete recovery is achieved.
For the treatment or prevention of post-operative, non-obstructive urinary retention:
-for treatment:
Intramuscular or Subcutaneous dosage:
Adults: 0.5 mg IM or subcutaneously. If no response is seen within 1 hour of the first dose, the patient should be catheterized. After the patient has voided, or the bladder has been emptied, continue 0.5 mg injections every 3 hours for at least 5 doses.
-for prevention:
Intramuscular or Subcutaneous dosage:
Adults: 0.25 mg IM or subcutaneously as soon as possible after the operation. Repeat every 4-6 hours for 2-3 days.
For the treatment of post-operative, non-obstructive abdominal distention (adynamic ileus):
Intramuscular or Subcutaneous dosage:
Adults: 0.5 mg IM or subcutaneously, as needed.
For the treatment of acute colonic pseudo-obstruction (Ogilvie's syndrome)*:
Intravenous dosage:
Adults: 2 to 2.5 mg IV infused over 3 to 5 minutes has been suggested in the reported literature. Consider repeat infusions in patients with an incomplete or temporary initial response. Other dosage regimens have been reported. Data from case reports and small, uncontrolled studies suggest neostigmine may reduce time to resolution vs. use of conservative management. Parasympathomimetic stimulation may produce serious adverse effects including profound bradycardia; therefore, cardiovascular monitoring (continuous telemetry) and atropine should be available. Per guidelines, neostigmine is the drug of choice for acute colonic pseudo-obstruction.
Maximum Dosage Limits:
-Adults
375 mg/day PO; 0.5 mg/dose IM or SC; 0.07 mg/kg or 5 mg total dose (whichever is less) IV.
-Geriatric
375 mg/day PO; 0.5 mg/dose IM or SC; 0.07 mg/kg or 5 mg total dose (whichever is less) IV.
-Adolescents
0.07 mg/kg or 5 mg total dose (whichever is less) IV; safety and efficacy of the PO, SC, and IM formulations have not been established.
-Children
0.07 mg/kg or 5 mg total dose (whichever is less) IV; safety and efficacy of the PO, SC, and IM formulations have not been established.
-Infants
0.07 mg/kg IV; safety and efficacy of the PO, SC, and IM formulations have not been established.
-Neonates
0.07 mg/kg total dose IV; safety and efficacy of the PO, SC, and IM formulations have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available. Neostigmine is metabolized by microsomal liver enzymes and hydrolyzed by cholinesterases. Theoretically hepatic impairment could hinder metabolism, although the clinical significance of this effect is not known. Initiate dosage cautiously; monitor for potential drug toxicity.
Patients with Renal Impairment Dosing
The FDA-approved product label for IV neostigmine methylsulfate states that dosage adjustments are not necessary in patients with renal impairment ; however, other sources suggest the following dosage adjustments:
CrCl > 50 ml/min: No dosage adjustment is needed.
CrCl 10-50 ml/min: Administer 50% of the dose at suggested dosing intervals for clinical indication.
CrCl < 10 ml/min: Administer 25% of the dose at suggested dosing intervals for clinical indication.
*non-FDA-approved indication
Acetaminophen; Ibuprofen: (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.
Acetylcholine Chloride: (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.
Albuterol; Budesonide: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Amifampridine: (Moderate) Coaministration of amifampridine and neostigmine 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.
Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Amlodipine; Celecoxib: (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.
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 neostigmine. 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 neostigmine. Intravenous neostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as atracurium.
Atropine: (Major) Coadministration of atropine and neostigmine may produce a mutually antagonistic effect.
Atropine; Difenoxin: (Major) Coadministration of atropine and neostigmine may produce a mutually antagonistic effect.
Azelastine; Fluticasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Beclomethasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of hyoscyamine.
Benztropine: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of benztropine. Benztropine might also antagonize some of the effects of neostigmine.
Betamethasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Bethanechol: (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.
Budesonide: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Budesonide; Formoterol: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy. (Minor) The muscarinic actions of neostigmine 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; 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.
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. (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.
Celecoxib: (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.
Celecoxib; Tramadol: (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.
Cevimeline: (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.
Chlordiazepoxide; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
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.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (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.
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 neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Cisatracurium: (Moderate) A higher cisatracurium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as neostigmine. Intravenous neostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as cisatracurium.
Clomipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
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.
Corticosteroids: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Cortisone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Deflazacort: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Desflurane: (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.
Desipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Dexamethasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Diclofenac: (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.
Diclofenac; Misoprostol: (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.
Dicyclomine: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of dicyclomine and vice-versa.
Diflunisal: (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.
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.
Diphenhydramine; Ibuprofen: (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.
Diphenhydramine; Naproxen: (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.
Diphenoxylate; Atropine: (Major) Coadministration of atropine and neostigmine may produce a mutually antagonistic effect.
Disopyramide: (Moderate) Disopyramide possesses clinically significant antimuscarinic properties and these appear to be dose-related. It is possible that disopyramide could antagonize the muscarinic actions of parasympathomimetics, including both the direct agonists and the cholinesterase-inhibitors. Clinicians should be alert to this possibility.
Doxepin: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Etodolac: (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.
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.
Fenoprofen: (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.
Fludrocortisone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Flunisolide: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Flurbiprofen: (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.
Fluticasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Fluticasone; Salmeterol: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Fluticasone; Vilanterol: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Formoterol; Mometasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Glycopyrrolate: (Minor) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
Glycopyrrolate; Formoterol: (Minor) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
Guanidine: (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.
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.
Homatropine; Hydrocodone: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of homatropine.
Hydrocodone; Ibuprofen: (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.
Hydrocortisone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Hyoscyamine: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of hyoscyamine.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of hyoscyamine.
Ibuprofen: (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.
Ibuprofen; Famotidine: (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.
Ibuprofen; Oxycodone: (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.
Ibuprofen; Pseudoephedrine: (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.
Imipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Indacaterol; Glycopyrrolate: (Minor) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
Indomethacin: (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.
Isoflurane: (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.
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.
Ketoprofen: (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.
Ketorolac: (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.
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; 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; 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.
Maprotiline: (Major) Maprotiline may antagonize some of the effects of neostigmine.
Mecamylamine: (Major) Ganglion-blockers, such as mecamylamine, can antagonize the effects of neostigmine. In addition, neostigmine might reduce the antihypertensive properties of mecamylamine.
Meclofenamate Sodium: (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.
Mefenamic Acid: (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.
Meloxicam: (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.
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.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) The muscarinic actions of neostigmine 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.
Methylprednisolone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Mometasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Nabumetone: (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.
Naproxen: (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.
Naproxen; Esomeprazole: (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.
Naproxen; Pseudoephedrine: (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.
Neostigmine; Glycopyrrolate: (Minor) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of glycopyrrolate.
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 (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Olopatadine; Mometasone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Oxaprozin: (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.
Oxybutynin: (Moderate) Oxybutynin is an antimuscarinic; the muscarinic actions of neostigmine 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 neostigmine. Intravenous neostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as pancuronium.
Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Coadministration of atropine and neostigmine may produce a mutually antagonistic effect. (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of hyoscyamine. (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of scopolamine.
Physostigmine: (Moderate) Neostigmine and physostigmine are both parasympathomimetics. Coadministration results in additive effects and should be done cautiously.
Pilocarpine: (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.
Piroxicam: (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.
Pralidoxime: (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.
Prednisolone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Prednisone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic 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: (Moderate) Procainamide may antagonize the effects of cholinesterase inhibitors such as neostigmine 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.
Propantheline: (Major) The muscarinic actions of neostigmine 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 (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Pyridostigmine: (Major) Neostigmine and pyridostigmine are both parasympathomimetics. Coadministration results in additive effects and should be done cautiously.
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 neostigmine. Intravenous neostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as rocuronium.
Ropivacaine: (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.
Scopolamine: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of scopolamine.
Sevoflurane: (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.
Succinylcholine: (Moderate) Neostigmine does not antagonize, and may prolong, the Phase I block of succinylcholine. If given before succinylcholine is metabolized by cholinesterase, neostigmine 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 neostigmine. Anticholinesterase drugs may not always be effective.
Sulindac: (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.
Sumatriptan; Naproxen: (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.
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.
Tolmetin: (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.
Triamcinolone: (Moderate) Concomitant use of anticholinesterase agents, such as neostigmine, and systemic corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating systemic corticosteroid therapy.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Trihexyphenidyl: (Major) The muscarinic actions of neostigmine can antagonize the antimuscarinic actions of trihexyphenidyl.
Trimipramine: (Moderate) Tricyclic antidepressants (TCAs) may antagonize some of the effects of parasympathomimetics (e.g., cholinesterase inhibitors) due to their anticholinergic activity. However, parasympathomimetics like bethanechol have occasionally been used historically to offset some of the adverse peripheral antimuscarinic (anticholinergic) effects of TCAs, such as dry mouth, constipation or urinary retention. For years, physostigmine was used as an adjunct to the treatment of TCA overdose; however, its efficacy was limited to addressing anticholinergic effects. Additionally, case reports suggest that harmful effects such as seizures and bradyarrhythmias progressing to asystole, especially in patients with cardiac conduction abnormalities at baseline, are possible. For these reasons, physostigmine is no longer considered a standard of care in the treatment of TCA overdose.
Vecuronium: (Moderate) A higher vecuronium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as neostigmine. Intravenous neostigmine is indicated for reversal of the effects of nondepolarizing neuromuscular blockers, such as vecuronium.
Neostigmine exerts its effects by competing with acetylcholine for its binding site on acetylcholinesterase. By interfering with acetylcholine enzymatic destruction, neostigmine potentiates the action of acetylcholine on both the skeletal muscle (nicotinic receptor) and the GI tract (muscarinic receptor). Neostigmine also can stimulate cholinergic responses in the eyes (causing miosis) if directly applied. Different muscle groups exhibit different levels of response to anticholinesterase agents, and doses that produce stimulation of one muscle group can cause weakness, through overdose, in another.
Specific responses to cholinesterase inhibitors include: increased skeletal muscle tone (nicotinic); increased gastric motility and GI tone (muscarinic); bradycardia (muscarinic); ureteral constriction (muscarinic); stimulation of the sweat and salivary glands (muscarinic); and constriction of the bronchi (muscarinic). There is also some evidence that they have a direct action on skeletal muscle.
Neostigmine methylsulfate also can be used to antagonize the effects of nondepolarizing neuromuscular blocking agents such as pancuronium and tubocurarine. Other uses include treating postoperative, nonobstructive urinary retention and postoperative, nonobstructive abdominal distension, for which bethanechol is used more commonly.
Neostigmine is administered intravenously, intramuscularly, subcutaneously, and orally. The drug has a volume of distribution between 0.12 and 1.4 L/kg, and does not readily cross the blood-brain barrier. Approximately 15 to 25% of neostigmine is bound to serum albumin. Neostigmine is metabolized by microsomal liver enzymes and hydrolyzed by cholinesterases. In adults, the half-life ranges from 42 to 60 minutes (mean of 52 minutes) for the oral formulation, 51 to 90 minutes for the intramuscular formulation, and 24 to 113 minutes for the intravenous formulation. Duration of effect varies considerably among patients. About 80% of the dose is excreted in the urine within 24 hours as parent drug and metabolites, with approximately 50% of the dose excreted unchanged.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Oral Route
Only 1 to 2% of neostigmine bromide is absorbed from the GI tract. As a general rule, 15 mg of neostigmine bromide orally is equivalent to 0.5 mg of neostigmine methylsulfate parenterally due to poor absorption of the tablet from the intestinal tract. Peak plasma concentrations occur in 1 to 2 hours after oral drug administration, with considerable individual variability. The onset of action occurs from 2 to 4 hours when taken orally.
Intravenous Route
When used for neuromuscular blocker reversal, doses of 0.03 to 0.07 mg/kg IV will generally achieve a train-of-four twitch ratio of 90% within 10 to 20 minutes of IV administration of neostigmine methylsulfate. The clinical effects last for 1-2 hours. Elimination half-life ranges from 24-113 minutes.
Intramuscular Route
Neostigmine methylsulfate is rapidly absorbed after intramuscular administration, with peak plasma concentrations observed at 30 minutes. Half-life ranges from 51-90 minutes. The onset of action occurs within 20 to 30 minutes after administration and last for a duration of 2.5 to 4 hours.
-Special Populations
Renal Impairment
Approximately 80% of a neostigmine dose is excreted in the urine as parent drug and metabolites, with approximately 50% of the dose excreted unchanged.The elimination half-life of neostigmine is prolonged in patients with end-stage renal disease. In a pharmacokinetic study of 18 adult patients, anephric patients had a plasma serum clearance of 7.8 ml/kg/min and an elimination half-life of 181.1 minutes compared to 16.7 ml/kg/min and 79.8 minutes in patients with normal renal function. Another study found that neostigmine methylsulfate's half-life increased from 79.8 (+/- 48.6) minutes in patients with normal renal function to 104.7 (+/- 64) minutes in transplant patients and 181 (+/- 54) minutes in anephric patients.
Pediatrics
Infants and Children
When compared to adults, infants and children require half the dose of neostigmine to produce comparable neuromuscular blockade antagonism. The time to produce 50% antagonism against a neuromuscular blocking agent (ED50) for infants (13.1 mcg/kg) and children (15.5 mcg/kg) is less than the value for adults (22.9 mcg/kg). Vd is similar for infants (0.54 L/kg), children (0.49 L/kg), and adults (0.52 L/kg); however, the elimination half-life for infants and children is significantly shorter. Elimination half-life is 39 +/- 5 minutes in infants, 48 +/- 16 minutes in children, and 67 +/- 8 minutes in adults. These differences are most likely due to higher plasma clearance values of infants (13.6 mL/kg/minute) and children (11.1 mL/kg/minute) compared to adults (9.6 mL/kg/minute). In addition, local differences at the neuromuscular junction (e.g., decreased enzyme activity, fewer acetylcholine reserves, limited receptor quantity) may explain lower dosage requirements in pediatric patients. Time to peak antagonism and duration of action is similar among age groups.