Bloxiverz Injection

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

. 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)]

. 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% (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.
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.

. 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.

. 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.

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.

.  Mechanism of Action

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.

.  Pharmacodynamics

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.

.  Pharmacokinetics

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.

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.