NEOSTIGMINE METHYLSULFATE injection

Country: United States

Language: English

Source: NLM (National Library of Medicine)

Active ingredient:

NEOSTIGMINE METHYLSULFATE (UNII: 98IMH7M386) (NEOSTIGMINE - UNII:3982TWQ96G)

Available from:

Amneal Pharmaceuticals LLC

Administration route:

INTRAVENOUS

Prescription type:

PRESCRIPTION DRUG

Therapeutic indications:

Neostigmine methylsulfate injection is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. Neostigmine methylsulfate is contraindicated in patients with: - known hypersensitivity to neostigmine methylsulfate (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis). - peritonitis or mechanical obstruction of the intestinal or urinary tract. Risk Summary There are no adequate or well-controlled studies of neostigmine methylsulfate in pregnant women. It is not known whether neostigmine methylsulfate 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 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. Risk Summary Neostigmine 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. Neostigmine methylsulfate 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 (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less). The dose of neostigmine methylsulfate 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. Because elderly patients are more likely to have decreased renal function, neostigmine methylsulfate 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 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)]. Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects. Although no adjustments to neostigmine methylsulfate 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. 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.  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 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, 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. 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.

Product summary:

Neostigmine methylsulfate injection, USP is a clear, colorless, sterile, nonpyrogenic solution intended for intravenous use. It is available as follows: 5 mg/10 mL (0.5 mg/mL) : 10 mL, Multiple-Dose Vial:                                       NDC 70121-1478-1 10 Vials in a Carton:                                                 NDC 70121-1478-7 10 mg/10 mL (1 mg/mL): 10 mL, Multiple-Dose Vial:                                       NDC 70121-1479-1 10 Vials in a Carton:                                                 NDC 70121-1479-7 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 between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Store in carton until time of use. Manufactured by: Amneal Pharmaceuticals Pvt. Ltd. Parenteral Unit Ahmedabad 382213, INDIA Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 02-2021-03

Authorization status:

Abbreviated New Drug Application

Summary of Product characteristics

NEOSTIGMINE METHYLSULFATE- NEOSTIGMINE METHYLSULFATE INJECTION
AMNEAL PHARMACEUTICALS LLC
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HIGHLIGHTS OF PRESCRIBING INFORMATION
THESE HIGHLIGHTS DO NOT INCLUDE ALL THE INFORMATION NEEDED TO USE
NEOSTIGMINE
METHYLSULFATE INJECTION SAFELY AND EFFECTIVELY. SEE FULL PRESCRIBING
INFORMATION FOR
NEOSTIGMINE METHYLSULFATE INJECTION.
NEOSTIGMINE METHYLSULFATE INJECTION, FOR INTRAVENOUS USE
INITIAL U.S. APPROVAL: 1939
INDICATIONS AND USAGE
Neostigmine methylsulfate injection, a cholinesterase inhibitor, is
indicated for the reversal of the effects
of non-depolarizing neuromuscular blocking agents (NMBAs) after
surgery. (1)
DOSAGE AND ADMINISTRATION
Should be administered by trained healthcare providers. (2.1)
Peripheral nerve stimulator and monitoring for twitch responses should
be used to determine when
neostigmine methylsulfate injection should be initiated and if
additional doses are needed. (2.2)
For reversal of NMBAs with shorter half-lives, when first twitch
response is substantially greater than
10% of baseline, or when a second twitch is present: 0.03 MG/KG BY
INTRAVENOUS ROUTE. (2.2)
For reversal of NMBAs with longer half-lives or when first twitch
response is close to 10% of baseline:
0.07 MG/KG BY INTRAVENOUS ROUTE. (2.2)
Maximum total dosage is 0.07 mg/kg or up to a total of 5 mg (whichever
is less). (2.2)
An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate,
should be administered prior to or
concomitantly with neostigmine methylsulfate injection. (2.4)
DOSAGE FORMS AND STRENGTHS
Injection: 0.5 mg/mL and 1 mg/mL in 10 mL multiple-dose vials. (3)
CONTRAINDICATIONS
Hypersensitivity to neostigmine. (4)
Peritonitis or mechanical obstruction of the intestinal or urinary
tract. (4)
WARNINGS AND PRECAUTIONS
Bradycardia: Atropine or glycopyrrolate should be administered prior
to neostigmine methylsulfate to
lessen risk of bradycardia. (5.1)
Serious Reactions with Coexisting Conditions: Use with caution in
patients with coronary artery disease,
cardiac arrhythmias, recent acute coronary syndro