Bloxiverz

BLOXIVERZ- neostigmine methylsulfate injection
Exela Pharma Sciences, LLC

1 INDICATIONS AND USAGE

BLOXIVERZ 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

BLOXIVERZ 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 BLOXIVERZ should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of BLOXIVERZ and should be used to determine the need for additional doses.

BLOXIVERZ is for intravenous use only and should be injected slowly over a period of at least 1 minute. The BLOXIVERZ dosage is weight-based [see Dosage and Administration ( 2.2)] .

Prior to BLOXIVERZ 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 BLOXIVERZ [see Dosage and Administration ( 2.4)]

2.2 Dosage in Adults

1. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using BLOXIVERZ.
2. 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 BLOXIVERZ.
3. Prior to administration, visually inspect BLOXIVERZ for particulate matter and discoloration.
4. BLOXIVERZ should be injected slowly by intravenous route over a period of at least 1 minute.
5. A 0.03 mg/kg to 0.07 mg/kg dose of BLOXIVERZ 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.
   1. The 0.03 mg/kg dose is recommended for:
      1. Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or
      2. When the first twitch response to the TOF stimulus is substantially greater than 10% of baseline or when a second twitch is present.
   2. The 0.07 mg/kg dose is recommended for
      1. NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or
      2. When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or
      3. There is need for more rapid recovery.
6. 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 BLOXIVERZ.
7. 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.
8. 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.
9. 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 BLOXIVERZ is administered to pediatric patients. Pediatric patients require BLOXIVERZ 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 BLOXIVERZ. 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 BLOXIVERZ.

3 DOSAGE FORMS AND STRENGTHS

BLOXIVERZ 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

BLOXIVERZ 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

5.1 Bradycardia

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

5.2 Serious Adverse Reactions in Patients with Certain Coexisting Conditions

BLOXIVERZ 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.

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 BLOXIVERZ administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of BLOXIVERZ 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 BLOXIVERZ. 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