Neostigmine Methylsulfate: Package Insert and Label Information

NEOSTIGMINE METHYLSULFATE- neostigmine methylsulfate injection
Xiromed LLC

1 INDICATIONS & USAGE

Neostigmine Methylsulfate Injection is a cholinesterase inhibitor indicated for the reversal of the effects of non­ depolarizing neuromuscular blocking agents after surgery.

2 DOSAGE & ADMINISTRATION

2.1. Important Dosage Information


Neostigmine Methylsulfate Injection should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses of Neostigmine Methylsulfate Injection should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of Neostigmine Methylsulfate Injection and should be used to determine the need for additional doses.
Neostigmine Methylsulfate Injection is for intravenous use only and should be injected slowly over a period of at least 1 minute. The Neostigmine Methylsulfate Injection dosage is weight-based [see Dosage and Administration (2.2)].
Prior to Neostigmine Methylsulfate Injection administration and until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Satisfactory recovery should be judged by adequacy of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation.An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with Neostigmine Methylsulfate Injection [see Dosage and Administration (2.4)]

2.2. Dosage in Adults

a. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using Neostigmine Methylsulfate Injection.
b. There must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level, i.e., the response prior to NMBA administration, prior to the administration of Neostigmine Methylsulfate Injection.
c. Prior to administration, visually inspect Neostigmine Methylsulfate Injection for particulate matter and discoloration.
d. Neostigmine Methylsulfate Injection should be injected slowly by intravenous route over a period of at least 1 minute.
e. A 0.03 mg/kg to 0.07 mg/kg dose of Neostigmine Methylsulfate Injection will generally achieve a TOF twitch ratio of 90% (TOF 0.9) within 10 to 20 minutes of administration. Dose selection should be based on the extent of spontaneous recovery that has occurred at the time of administration, the half-life of the NMBA being reversed, and whether there is a need to rapidly reverse the NMBA.
• The 0.03 mg/kg dose is recommended for:
i. Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or
ii. When the first twitch response to the TOF stimulus is substantially greater than 10% of baseline or when a second twitch is present.
• The 0.07 mg/kg dose is recommended for
iii. NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or
iv. When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or
v. There is need for more rapid recovery.
f. TOF monitoring should continue to be used to evaluate the extent of recovery of neuromuscular function and the possible need for an additional dose of Neostigmine Methylsulfate Injection.
g. TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to adequately ventilate and maintain a patent airway following tracheal extubation.
h. Patients should continue to be monitored for adequacy of reversal from NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used.
i. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less.

2.3. Dosage in Pediatric Patients, including Neonates

Adult guidelines should be followed when Neostigmine Methylsulfate Injection is administered to pediatric patients. Pediatric patients require Neostigmine Methylsulfate Injection doses similar to those for adult patients.

2.4. Anticholinergic (Atropine or Glycopyrrolate) Administration


An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with Neostigmine Methylsulfate Injection. The anticholinergic agent should be administered intravenously using a separate syringe. In the presence of bradycardia, it is recommended that the anticholinergic agent be administered prior to Neostigmine Methylsulfate Injection.

3 DOSAGE FORMS & STRENGTHS

Neostigmine Methylsulfate Injection, USP is available as

· Injection: 0.5 mg/mL, 5 mg of neostigmine methylsulfate in 10 mL multiple- dose vials

· Injection: 1 mg/mL, 10 mg of neostigmine methylsulfate in 10 mL multiple-dose vials

4 CONTRAINDICATIONS


Neostigmine Methylsulfate Injection 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).• with peritonitis or mechanical obstruction of the intestinal or urinary tract.

5 WARNINGS AND PRECAUTIONS

5.1. Bradycardia

Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to Neostigmine Methylsulfate Injection to lessen the risk of bradycardia [see Dosage and Administration (2.4)].

5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions

Neostigmine Methylsulfate Injection should be used with caution in patients with coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. Because of the known pharmacology of neostigmine methylsulfate as an acetylcholinesterase inhibitor, cardiovascular effects such asbradycardia, hypotension or dysrhythmia would be anticipated. In patients with certain cardiovascular conditions such as coronary artery disease, cardiac arrhythmias or recent acute coronary syndrome, the risk of blood pressure and heart rate complications may be increased. Risk of these complications may also be increased in patients with myasthenia gravis. Standard antagonism with anticholinergics (e.g., atropine) is generally successful to mitigate the risk of cardiovascular complications.

5.3. Hypersensitivity

Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available.

5.4. Neuromuscular Dysfunction

Large doses of Neostigmine Methylsulfate Injection administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of Neostigmine Methylsulfate Injection should be reduced if recovery from neuromuscular blockade is nearly complete.

5.5. Cholinergic Crisis

It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of Neostigmine Methylsulfate Injection. Both conditions result in extreme muscle weakness but require radically different treatment. [see Overdosage (10)]

6 ADVERSE REACTIONS

6.1. Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions to neostigmine methylsulfate are most often attributable to exaggerated pharmacological effects, in particular, at muscarinic receptor sites. The use of an anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, may prevent or mitigate these reactions.

Quantitative adverse event data are available from trials of neostigmine methylsulfate in which 200 adult patients were exposed to the product. The following table lists the adverse reactions that occurred with an overall frequency of 1% or greater.

System Organ Class Adverse Reaction
Cardiovascular Disorders bradycardia, hypotension, tachycardia/heart rate increase
Gastrointestinal Disorders dry mouth, nausea, post-procedural nausea, vomiting
General Disorders and Administration Site Conditions incision site complication, pharyngolaryngeal pain, procedural complication, procedural pain
Nervous System Disorders dizziness, headache, postoperative shivering, prolonged neuromuscular blockade
Psychiatric Disorders insomnia
Respiratory, Thoracic and Mediastinal Disorders dyspnea, oxygen desaturation <90%
Skin and Subcutaneous Tissue Disorders pruritus

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 ofconsciousness, 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 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 occurred at HED doses up 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 Labor & Delivery

The effect of Neostigmine Methylsulfate Injection on the mother and fetus with regard to labor, delivery, the need for forceps delivery or other intervention or resuscitation of the newborn, is not known.

Cholinesterase inhibitor drugs may induce premature labor when given intravenously to pregnant women near term.

8.3 Nursing Mothers

It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when Neostigmine Methylsulfate Injection is administered to a nursing woman.

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 — 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)].

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