DailyMed Label: Bloxiverz

DailyMed Label: Bloxiverz

2023

DailyMed Prescription

Bloxiverz

Neostigmine Methylsulfate

Exela Pharma Sciences, LLC

NDC: 51754-1210

NDC: 51754-1220

NDC: 51754-1200

NDC: 51754-1200

NDC: 51754-1200

NDC: 51754-1210

NDC: 51754-1210

NDC: 51754-1220

NDC: 51754-1220

NDC: 51754-1200

NDC: 51754-1200

Neostigmine methylsulfate, a cholinesterase inhibitor, is ( m -hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is: Neostigmine methylsulfate is a white crystalline powder and is very soluble in water and soluble in alcohol. BLOXIVERZ is a sterile, nonpyrogenic solution intended for intravenous use. Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate 0.5 mg, phenol 4.5 mg (used as preservative) and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5. Each mL of the 1 mg/mL strength contains neostigmine methylsulfate 1 mg, phenol 4.5 mg (used as preservative), and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5. Each mL of the 5 mL single-dose prefilled syringe contains 1 mg neostigmine methylsulfate, USP, 90 mg sodium chloride, USP and 1 mg sodium acetate trihydrate, USP in water for injection. May contain sodium hydroxide, NF and/or glacial acetic acid, USP as needed for pH adjustment to achieve a value of 5.5. structure

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 ( 1 ).

• Should be administered by trained healthcare providers ( 2.1 ) • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when BLOXIVERZ should be initiated and if additional doses are needed ( 2.2 ) 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 ( 2.2 ) 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 ( 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 BLOXIVERZ ( 2.4 ) 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 )] 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. Adult guidelines should be followed when BLOXIVERZ is administered to pediatric patients. Pediatric patients require BLOXIVERZ doses similar to those for adult patients. 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. 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. (See Figure 1): 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

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 • Injection: 1 mg/mL, 5 mg of neostigmine methylsulfate in 5 mL single-dose prefilled syringe. Injection: 0.5 mg/mL and 1 mg/mL in 10 mL multiple-dose vials and 1 mg/mL in 5 mL single-dose prefilled syringe ( 3 )

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 ( 4 ) • Peritonitis or mechanical obstruction of the intestinal or urinary tract ( 4 )

• Bradycardia: Atropine or glycopyrrolate should be administered prior to BLOXIVERZ 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 syndrome or myasthenia gravis. ( 5.2 ) • 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. ( 5.4 ) 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 )] . 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. Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available. 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. 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 )] .

Most common adverse reactions during treatment: bradycardia, nausea and vomiting. (

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 BLOXIVERZ with other drugs which may alter the activity of metabolizing enzymes or transporters.

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. Risk Summary Published data from case reports are insufficient to determine the presence of neostigmine methylsulfate in human milk or the effects on the breastfed infant. There is no information on the effects of neostigmine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for BLOXIVERZ and any potential adverse effects on the breastfed infant from BLOXIVERZ or from the underlying maternal condition. BLOXIVERZ 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 BLOXIVERZ (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less). The dose of BLOXIVERZ 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. Because elderly patients are more likely to have decreased renal function, BLOXIVERZ 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 BLOXIVERZ 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 BLOXIVERZ 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 BLOXIVERZ. 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 BLOXIVERZ 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 BLOXIVERZ, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of BLOXIVERZ. 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.

BLOXIVERZ (Neostigmine Methylsulfate Injection, USP) is available in the following: NDC No. Strength Vial Size 51754-1210-3 0.5 mg/mL 10 mL multiple-dose vials (supplied in packages of 10) 51754-1220-3 1 mg/mL 10 mL multiple-dose vials (supplied in packages of 10) 51754-1200-3 1 mg/mL 5 mL single-dose prefilled syringe (supplied in packages of 10) The vial stopper is not made with natural rubber latex. BLOXIVERZ should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Protect from light. Store in carton until time of use. Manufactured for: Exela Pharma Sciences, LLC Lenoir, NC 28645 Logo

Neostigmine methylsulfate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, neostigmine methylsulfate induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as nondepolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade. Neostigmine methylsulfate-induced increases in acetylcholine levels results in the potentiation of both muscarinic and nicotinic cholinergic activity. The resulting elevation of acetylcholine competes with nondepolarizing neuromuscular blocking agents to reverse neuromuscular blockade. Neostigmine methylsulfate does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system. Distribution: Following intravenous injection, the observed neostigmine methylsulfate volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of neostigmine methylsulfate to human serum albumin ranges from 15 to 25%. Metabolism: Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Elimination: Following intravenous injection, the reported elimination half-life of neostigmine methylsulfate is between 24 and 113 minutes. Total body clearance of neostigmine methylsulfate is reported between 1.14 and 16.7 mL/min/kg. Renal impairment: Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects; elimination half-life for normal, transplant and anephric patients were 79.8 ± 48.6, 104.7 ± 64 and 181 ± 54 min (mean ± SD), respectively. Hepatic impairment: The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment has not been studied. Pediatrics: Elimination half-life of neostigmine methylsulfate in infants (2-10 months), children (1-6 years) and adults (29-48 years) were 39 ± 5 min, 48 ± 16 min, and 67 ± 8 min (mean ± SD), respectively. Observed neostigmine methylsulfate clearance for infants, children and adults were 14 ± 3, 11 ± 3 and 10 ± 2 mL/min/kg (mean ± SD), respectively. Drug Interaction Studies: The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied.

Carcinogenesis: Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine. Genotoxicity: Neostigmine methylsulfate was not mutagenic or clastogenic when evaluated in an in vitro bacterial reverse mutation assay (Ames test), an in vitro Chinese hamster ovary cell chromosomal aberration assay, or an in vivo mouse bone marrow micronucleus assay. Impairment of Fertility: In a fertility and early embryonic development study in rats, male rats were treated for 28 days prior to mating and female rats were treated for 14 days prior to mating with intravenous neostigmine methylsulfate (human equivalent doses of 1.6, 4, and 8.1 mcg/kg/day, based on body surface area). No adverse effects were reported at any dose (up to 0.1 times the MRHD of 5 mg/60 kg person based on a body surface area comparison).

The evidence for the efficacy of neostigmine methylsulfate for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery is derived from the published literature. Randomized, spontaneous-recovery or placebo-controlled studies using similar efficacy endpoints evaluated a total of 404 adult and 80 pediatric patients undergoing various surgical procedures. Patients had reductions in their recovery time from neuromuscular blockade with neostigmine methylsulfate treatment compared to spontaneous recovery.

NDC 51754-1210-1 Bloxiverz (Neostigmine Methylsulfate Injection, USP) 5 mg/10 mL (0.5 mg/mL) For Intravenous Use 10 mL Multiple-Dose Vial 0.5 mg vial