Bloxiverz

1 INDICATIONS AND USAGE BLOXIVERZ, is a cholinesterase inhibitor, indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. BLOXIVERZ, is a cholinesterase inhibitor, indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.

2 DOSAGE AND ADMINISTRATION • Should be administered by trained healthcare providers • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when BLOXIVERZ should be initiated and if additional doses are needed o 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 o 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 • Maximum total dosage is 0.07 mg/kg or up to a total of 5 mg (whichever is less) • An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ 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 . 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

2.2Dosage in Adults

a. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using BLOXIVERZ. 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 BLOXIVERZ. c.

Prior to administration, visually inspect BLOXIVERZ for particulate matter and discoloration. d. BLOXIVERZ 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 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. 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 BLOXIVERZ. 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.

2.3Dosage 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.

2.4Anticholinergic

(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.

2.5Instructions for Use of Prefilled Syringe

1. Perform visual inspection on the syringe by verifying: • Absence of syringe damage • Absence of external particles • Absence of internal particles • Proper drug color • Drug name • Drug strength • Fill volume • Route of administration • Expiration date to be sure the drug has not expired 2. Do not remove the tamper evident seal.

Push plunger rod slightly in to break the stopper loose while tip cap is still on 3. Remove tip cap and tamper evident seal by twisting off. : Figure 1. 4. Discard the tip cap. 5. Expel air bubble. 6. Adjust dose into sterile material (if applicable). 7. Connect the syringe to an appropriate intravenous connection. • Before injection, ensure that the syringe is securely attached to the needle or needleless luer access device (NLAD). 8.

Depress plunger rod to deliver medication. Ensure that pressure is maintained on the plunger rod during the entire administration. 9. Remove syringe from NLAD (if applicable) and discard into appropriate receptacle. • To prevent needle stick injuries, do not recap needle when needle is connected to syringe.

NOTES: All steps must be done sequentially - Do not re-sterilize syringe - Do not use this product on a sterile field - Do not introduce any other fluid into the syringe at any time - This product is for single dose only instruction

5 WARNINGS AND PRECAUTIONS • Bradycardia: Atropine or glycopyrrolate should be administered prior to BLOXIVERZ to lessen risk of bradycardia. • Serious Reactions with Coexisting Conditions: Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. • Neuromuscular Dysfunction: Can occur if large doses of BLOXIVERZ are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete.

5.1Bradycardia Neostigmine

has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to BLOXIVERZ to lessen the risk of bradycardia .

5.2Serious 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.

5.3Hypersensitivity Because of the

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

5.4Neuromuscular 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.

5.5Cholinergic 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 .

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. • Hypersensitivity to neostigmine • Peritonitis or mechanical obstruction of the intestinal or urinary tract

8.1Pregnancy Risk Summary Published

studies and case reports over several decades about the use of neostigmine products, including neostigmine methylsulfate, in pregnant women have not identified any drug-associated risk for major birth defects and miscarriage. However, most of the available data are based on studies with exposure that occurred at the time of caesarean section or labor and delivery. These studies have not identified an adverse effect on maternal or infant outcomes.

In animal reproduction studies, no adverse developmental effects were observed after administration of neostigmine methylsulfate to pregnant rats and rabbits during organogenesis with doses up to 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD) of 5mg/60kg/person/day based on body surface area (mg/m 2 ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20% respectively. Data Animal Data In embryofetal development studies, rats and rabbits were administered neostigmine methylsulfate at human equivalent doses (HED, on a mg/m 2 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/m 2 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.

Most common adverse reactions during treatment: bradycardia, nausea and vomiting. To report SUSPECTED ADVERSE REACTIONS, contact Exela Pharma Sciences, LLC at 1-888-451-4321 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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

6.2Post 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 of consciousness, 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