Neostigmine Methylsulfate (Page 3 of 3)

10 OVERDOSAGE


Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of neostigmine methylsulfate injection (cholinergic crisis), but may be managed by the use of additional atropine or glycopyrrolate. The possibility of iatrogenic overdose can be lessened by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored.
Overdosage of neostigmine methylsulfate injection can cause cholinergic crisis, which is characterized by increasing muscle weakness, and through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish from cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of neostigmine methylsulfate injection or other drugs in this class, in the presence of cholinergic crisis or of a refractory or “insensitive” state, could have grave consequences. The two types of crises may be differentiated by the use of edrophonium chloride as well as by clinical judgment.
Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is also recommended. Atropine may also be used to lessen gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.

11 DESCRIPTION

Neostigmine methylsulfate, a cholinesterase inhibitor, is (m -hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is:

neostr

Neostigmine methylsulfate USP is a white powder and is very soluble in water and freely soluble in ethanol (96%). Neostigmine methylsulfate USP is a sterile, nonpyrogenic solution intended for intravenous use.
Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate USP 0.5 mg, phenol 4.5 mg (used as preservative) and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5.
Each mL of the 1 mg/mL strength contains neostigmine methylsulfate USP 1 mg, phenol 4.5 mg (used as preservative), and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Neostigmine methylsulfate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, neostigmine methylsulfate induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as non-depolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade.

12.2 Pharmacodynamics

Neostigmine methylsulfate-induced increases in acetylcholine levels results in the potentiation of both muscarinic and nicotinic cholinergic activity. The resulting elevation of acetylcholine competes with non-depolarizing neuromuscular blocking agents to reverse neuromuscular blockade. Neostigmine methylsulfate does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system.

12.3 Pharmacokinetics


Distribution: Following intravenous injection, the observed neostigmine methylsulfate volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of neostigmine methylsulfate to human serum albumin ranges from 15 to 25%.
Metabolism: Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver.
Elimination: Following intravenous injection, the reported elimination half-life of neostigmine methylsulfate is between 24 and 113 minutes. Total body clearance of neostigmine methylsulfate is reported between 1.14 and 16.7 mL/min/kg.
Renal impairment: Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects; elimination half-life for normal, transplant and anephric patients were 79.8 ± 48.6, 104.7 ± 64 and 181 ± 54 min (mean ± SD), respectively.
Hepatic impairment: The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment has not been studied.
Pediatrics: Elimination half-life of neostigmine methylsulfate in infants (2 to 10 months), children (1 to 6 years) and adults (29 to 48 years) were 39 ± 5 min, 48 ± 16 min, and 67 ± 8 min (mean ± SD), respectively. Observed neostigmine methylsulfate clearance for infants, children and adults were 14 ± 3, 11 ± 3 and 10 ± 2 mL/min/kg (mean ± SD), respectively. Drug Interaction Studies: The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine.
Genotoxicity: Neostigmine methylsulfate was not mutagenic or clastogenic when evaluated in an in vitro bacterial reverse mutation assay (Ames test), an in vitro Chinese hamster ovary cell chromosomal aberration assay, or an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility: In a fertility and early embryonic development study in rats, male rats were treated for 28 days prior to mating and female rats were treated for 14 days prior to mating with intravenous neostigmine methylsulfate (human equivalent doses of 1.6, 4, and 8.1 mcg/kg/day, based on body surface area). No adverse effects were reported at any dose (up to 0.1 times the MRHD of 5 mg/60 kg person based on a body surface area comparison).

14 CLINICAL STUDIES

The evidence for the efficacy of neostigmine methylsulfate for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery is derived from the published literature. Randomized, spontaneous-recovery or placebo-controlled studies using similar efficacy endpoints evaluated a total of 404 adult and 80 pediatric patients undergoing various surgical procedures. Patients had reductions in their recovery time from neuromuscular blockade with neostigmine methylsulfate treatment compared to spontaneous recovery.

16 HOW SUPPLIED/STORAGE AND HANDLING

Neostigmine methylsulfate injection, USP is a clear, colourless solution free from visible particles in a glass vial. It is available as follows:

NDC No. Strength Vial Size
72572-460-240.5 mg/mL 10 mL multiple-dose vials (supplied in packages of 24)
72572-461-241 mg/mL 10 mL multiple-dose vials (supplied in packages of 24)

The vial stopper is not made with natural rubber latex.
Neostigmine Methylsulfate Injection, USP should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Protect from light. Store in carton until time of use.

Distributed by:
Civica, Inc.
Lehi, Utah 84043
Manufactured by:
neobelogo
Biological E. Limited
Plot No.4, Survey no. 542/P, Biotech Park Phase-II,
Kolthur Village, Shameerpet Mandal,
Medchal, Telangana 500078, India.
Revised: May 2021
20001799

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Neostigmine Methylsulfate Injection USP, 5 mg/10 mL (0.5 mg/mL) — Vial Label

neo5mgviallabel
(click image for full-size original)

Neostigmine Methylsulfate Injection USP, 5 mg/10 mL (0.5 mg/mL) — Carton Label
neo5mgper10mlcartonlabel
(click image for full-size original)

Neostigmine Methylsulfate Injection USP, 5 mg/10 mL (0.5 mg/mL) — 24s Outer Carton Label
neo5mgper10ml24cartonlabel
(click image for full-size original)

Neostigmine Methylsulfate Injection USP, 10 mg/10 mL (1 mg/mL) — Vial Label
neo10mgviallabel
(click image for full-size original)

Neostigmine Methylsulfate Injection USP, 10 mg/10 mL (1 mg/mL) — Carton Label
neo10mgper10mlcartonlabel
(click image for full-size original)

Neostigmine Methylsulfate Injection USP, 10 mg/10 mL (1 mg/mL) — 24s Outer Carton Label
neo10mgper10ml24scartonlabel
(click image for full-size original)

NEOSTIGMINE METHYLSULFATE neostigmine methylsulfate injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72572-460
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
NEOSTIGMINE METHYLSULFATE (NEOSTIGMINE) NEOSTIGMINE METHYLSULFATE 0.5 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
PHENOL 4.5 mg in 1 mL
SODIUM ACETATE 0.2 mg in 1 mL
ACETIC ACID
SODIUM HYDROXIDE
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:72572-460-24 24 CARTON in 1 CARTON contains a CARTON (72572-460-01)
1 NDC:72572-460-01 1 VIAL, MULTI-DOSE in 1 CARTON This package is contained within the CARTON (72572-460-24) and contains a VIAL, MULTI-DOSE
1 10 mL in 1 VIAL, MULTI-DOSE This package is contained within a CARTON (72572-460-01) and a CARTON (72572-460-24)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA212512 05/13/2019
NEOSTIGMINE METHYLSULFATE neostigmine methylsulfate injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72572-461
Route of Administration INTRAVENOUS DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
NEOSTIGMINE METHYLSULFATE (NEOSTIGMINE) NEOSTIGMINE METHYLSULFATE 1 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
PHENOL 4.5 mg in 1 mL
SODIUM ACETATE 0.2 mg in 1 mL
ACETIC ACID
SODIUM HYDROXIDE
WATER
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:72572-461-24 24 CARTON in 1 CARTON contains a CARTON (72572-461-01)
1 NDC:72572-461-01 1 VIAL, MULTI-DOSE in 1 CARTON This package is contained within the CARTON (72572-461-24) and contains a VIAL, MULTI-DOSE
1 10 mL in 1 VIAL, MULTI-DOSE This package is contained within a CARTON (72572-461-01) and a CARTON (72572-461-24)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA212512 05/13/2019
Labeler — Civica Inc. (081373942)
Establishment
Name Address ID/FEI Operations
Biological E. Limited 871410645 ANALYSIS (72572-460), ANALYSIS (72572-461), MANUFACTURE (72572-460), MANUFACTURE (72572-461)

Revised: 08/2021 Civica Inc.

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