NEOSTIGMINE METHYLSULFATE- neostigmine methylsulfate injection
Hikma Pharmaceuticals USA Inc.
1. INDICATIONS AND USAGE
Neostigmine Methylsulfate Injection, USP is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.
2. DOSAGE AND ADMINISTRATION
2.1. Important Dosage Information
Neostigmine Methylsulfate Injection, USP 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, USP should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of Neostigmine Methylsulfate Injection, USP and should be used to determine the need for additional doses.
Neostigmine Methylsulfate Injection, USP is for intravenous use only and should be injected slowly over a period of at least 1 minute. The Neostigmine Methylsulfate Injection, USP dosage is weight-based [see Dosage and Administration (2.2)].
Prior to Neostigmine Methylsulfate Injection, USP 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, USP [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, USP.
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, USP.
c. Prior to administration, visually inspect Neostigmine Methylsulfate Injection, USP for particulate matter and discoloration.
d. Neostigmine Methylsulfate Injection, USP 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, USP will generally achieve a TOF twitch ratio of 90% (TOF0.9 ) 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:
– Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or
– 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:
– NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or
– When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or
– 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, USP.
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, USP is administered to pediatric patients. Pediatric patients require Neostigmine Methylsulfate Injection, USP 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, USP. 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, USP.
3. DOSAGE FORMS AND 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
Neostigmine Methylsulfate Injection, USP 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.
5. WARNINGS AND PRECAUTIONS
Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to Neostigmine Methylsulfate Injection, USP 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, USP 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 as bradycardia, 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.
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, USP administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of Neostigmine Methylsulfate Injection, USP 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, USP. 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|
|Respiratory, Thoracic and Mediastinal Disorders||dyspnea, oxygen desaturation <90%|
|Skin and Subcutaneous Tissue Disorders||pruritus|
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