Neostigmine Methylsulfate (Page 2 of 3)

6.2 Post Marketing Experience

The following adverse reactions have been identified during parenteral use of neostigmine methylsulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

System Organ Class Adverse Reaction
Allergic Disorders allergic reactions, anaphylaxis
Nervous System Disorders convulsions, drowsiness, dysarthria, fasciculation, loss of consciousness, miosis, visual changes
Cardiovascular Disorders cardiac arrest, cardiac arrhythmias (A-V block, nodal rhythm), hypotension, nonspecific EKG changes, syncope
Respiratory, Thoracic and Mediastinal Disorders bronchospasm; increased oral, pharyngeal and bronchial secretions; respiratory arrest; respiratory depression
Skin and Sub-cutaneous Tissue Disorders rash, urticaria
Gastrointestinal Disorders bowel cramps, diarrhea, flatulence, increased peristalsis
Renal and Urinary Disorders urinary frequency
Musculoskeletal and Connective Tissue Disorders arthralgia, muscle cramps, spasms, weakness
Miscellaneous diaphoresis, flushing

7 DRUG INTERACTIONS

The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Use with caution when using neostigmine methylsulfate injection with other drugs which may alter the activity of metabolizing enzymes or transporters.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy


Risk Summary
There are no adequate or well-controlled studies of neostigmine methylsulfate injection in pregnant women. It is not known whether neostigmine methylsulfate injection can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. The incidence of malformations in human pregnancies has not been established for neostigmine as the data are limited. All pregnancies, regardless of drug exposure, have a background risk of 2 to 4% for major birth defects, and 15 to 20% for pregnancy loss.
No adverse effects were noted in rats or rabbits treated with human equivalent doses of neostigmine methylsulfate doses up to 8.1 and 13 mcg/kg/day, respectively, during organogenesis (0.1 to 0.2 times the maximum recommended human dose of 5 mg/60 kg person/day based on body surface area comparisons).
Anticholinesterase drugs, including neostigmine may cause uterine irritability and induce premature labor when administered to pregnant women near term.
Neostigmine methylsulfate injection should be given to a pregnant woman only if clearly needed.
Data
Animal Data
In embryofetal development studies, rats and rabbits were administered neostigmine methylsulfate at human equivalent doses (HED, on a mg/m2 basis) of 1.6, 4 and 8.1 mcg/kg/day and 3.2, 8.1, and 13 mcg/kg/day, respectively, during the period of organogenesis (Gestation Days 6 through 17 for rats and Gestation Days 6 through 18 for rabbits). There was no evidence for a teratogenic effect in rats and rabbits up to HED 8.1 and 13 mcg/kg/day, which are approximately 0.097 times and 0.16 times the MRHD of 5 mg/60 kg, respectively in the presence of minimal maternal toxicity (tremors, ataxia, and prostration). The studies resulted in exposures in the animals well below predicted exposures in humans. In a pre- and postnatal development study in rats, neostigmine methylsulfate was administered to pregnant female rats at human equivalent doses (HED) of 1.6, 4 and 8.1 mcg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21. There were no adverse effects on physical development, behavior, learning ability, or fertility in the offspring at HED doses up to 8.1 mcg/kg/day which is 0.097 times the MRHD of 5 mg/60 kg on a mg/m2 basis in the presence of minimal maternal toxicity (tremors, ataxia, and prostration). The studies resulted in exposures in the animals well below predicted exposures in humans.

8.2 Lactation

Risk SummaryNeostigmine methylsulfate has not been studied in lactating women. It is not known whether neostigmine methylsulfate is present in human milk, or if neostigmine methylsulfate has effects on milk production or the breastfed child. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s need for neostigmine methylsulfate and any potential adverse effects on the breastfed child from neostigmine methylsulfate or from the underlying maternal condition.

8.4 Pediatric Use

Neostigmine methylsulfate injection is approved for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery in pediatric patients of all ages.
Recovery of neuromuscular activity occurs more rapidly with smaller doses of cholinesterase inhibitors in infants and children than in adults. However, infants and small children may be at greater risk of complications from incomplete reversal of neuromuscular blockade due to decreased respiratory reserve. The risks associated with incomplete reversal outweigh any risk from giving higher doses of neostigmine methylsulfate injection (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less).
The dose of neostigmine methylsulfate injection required to reverse neuromuscular blockade in children varies between 0.03 mg to 0.07 mg/kg, the same dose range shown to be effective in adults, and should be selected using the same criteria as used for adult patients [see Clinical Pharmacology (12.3)].
Since the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate, the effects of an anticholinergic agent (e.g., atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension.

8.5 Geriatric Use

Because elderly patients are more likely to have decreased renal function, neostigmine methylsulfate injection should be used with caution and monitored for a longer period in elderly patients. The duration of action of neostigmine methylsulfate is prolonged in the elderly; however, elderly patients also experience slower spontaneous recovery from neuromuscular blocking agents. Therefore, dosage adjustments are not generally needed in geriatric patients; however, they should be monitored for longer periods than younger adults to assure additional doses of neostigmine methylsulfate injection are not required. The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient [see Dosage and Administration (2.3)].

8.6 Renal Impairment


Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects.
Although no adjustments to neostigmine methylsulfate injection dosing appear to be warranted in patients with impaired renal function, they should be closely monitored to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of neostigmine methylsulfate injection. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended.

8.7 Hepatic Impairment

The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment have not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. No adjustments to the dosing of neostigmine methylsulfate injection appear to be warranted in patients with hepatic insufficiency. However, patients should be carefully monitored if hepatically cleared neuromuscular blocking agents were used during their surgical procedure as their duration of action may be prolonged by hepatic insufficiency whereas neostigmine methylsulfate injection, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of neostigmine methylsulfate injection. This same situation may arise if the neuromuscular blocking agent has active metabolites. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended.

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