Prescription Drugs

CLINICAL PHARMACOLOGY Neostigmine inhibits the hydrolysis of acetylcholine by competing with acetylcholine for attachment to acetylcholinesterase at sites of cholinergic transmission.It enhances cholinergic action by facilitating the transmission of impulses across neuromuscular junctions. It also has a direct cholinomimetic effect on skeletal muscle and possibly on autonomic ganglion cells and neurons of the central nervous system. Neostigmine undergoes hydrolysis by cholinesterase and is also metabolized by microsomal enzymes in the liver.Protein binding to human serum albumin ranges from 15 to 25 percent. Following intramuscular administration, Neostigmine is rapidly absorbed and eliminated.In a study of five patients with myasthenia gravis, peak plasma levels were observed at 30 minutes, and the half-life ranged from 51 to 90 minutes. Approximately 80 percent of the drug was eliminated in urine within 24 hours; approximately 50% as the unchanged drug and 30 percent as metabolites. Following intravenous administration, plasma half-life ranges from 47 to 60 minutes have been reported with a mean half-life of 53 minutes. The clinical effects of Neostigmine usually begin within 20 to 30 minutes after intramuscular injection and last from 2.5 to 4 hours.

CLINICAL PHARMACOLOGY 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. Clinical Studies The evidence for the efficacy of neostigmine methylsulfate for the reversal of the effects of nondepolarizing 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.

Find Lowest Prices on Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) Injection Injection, USP DESCRIPTION Neostigmine Methylsulfate Injection, USP is the dimethylcarbamate of (m-hydroxyphenyl) trimethylammonium methylsulfate. The structural formula is: C13H22N2O6S............................Molecular Weight 334.40 Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) , an anticholinesterase agent, is a bitter tasting, white crystalline powder and is very soluble in water and soluble in alcohol. Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP is a sterile, nonpyrogenic solution intended for intramuscular, subcutaneous or slow intravenous use. Each mL of the 1:1000 concentration contains Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) 1 mg, Methylparaben 1.8 mg and Propylparaben 0.2 mg (used as preservatives), in Water for Injection q.s.pH (range 5.0 - 6.5) adjusted, when necessary, with Sodium Hydroxide. Each mL of the 1:2000 concentration contains Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) 0.5 mg, Methylparaben 1.8 mg and Propylparaben 0.2 mg (used as preservatives), in Water for Injection q.s.pH (range 5.0 - 6.5) adjusted, when necessary, with Sodium Hydroxide.

Find Lowest Prices on BLOXIVERZ (neostigmine methylsulfate) Injection for Intravenous Use DESCRIPTION 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.

INDICATIONS Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP is indicated for: - the symptomatic control of myasthenia gravis when oral therapy is impractical. - the prevention and treatment of postoperative distention and urinary retention after mechanical obstruction has been excluded. - reversal of effects of non-depolarizing neuromuscular blocking agents (e.g., tubocurarine, metocurine, gallamine or pancuronium) after surgery. DOSAGE AND ADMINISTRATION Symptomatic control of myasthenia gravis: One mL of the 1:2000 solution (0.5 mg) subcutaneously or intramuscularly. Subsequent doses should be based on the individual patient's response.In most patients, however, oral treatment with Neostigmine Bromide tablets, 15 mg each, is adequate for control of symptoms. Prevention of postoperative distention and urinary retention: 0.25 mg subcutaneously or intramuscularly as soon as possible after operation;repeat every 4 to 6 hours for two or three days. Treatment of postoperative distention: One mL of the 1:2000 solution (0.5 mg) subcutaneously or intramuscularly, as required. Treatment of urinary retention: One mL of the 1:2000 solution (0.5 mg) subcutaneously or intramuscularly. If urination does not occur within an hour, the patient should be catheterized.After the patient has voided, or the bladder has been emptied, continue the 0.5 mg injections every three hours for at least 5 injections. Reversal of Effects of Non-depolarizing Blocking Agents: When Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP is administered intravenously, it is recommended that Atropine Sulfate (0.6 to 1.2 mg) also be given intravenously using separate syringes.Some authorities have recommended that the Atropine be injected several minutes before the Neostigmine rather than concomitantly. The usual dose is 0.5 to 2 mg Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP given by slow intravenous injection, repeated as required.Only in exceptional cases should the total dose of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) exceed 5 mg.It is recommended that the patient be well ventilated and a patent airway maintained until complete recovery of normal respiration is assured.The optimum time for administration of the drug is during hyperventilation when the carbon dioxide level of the blood is low. It should never be administered in the presence of high concentrations of halothane or cyclopropane.In cardiac cases and severely ill patients, it is advisable to titrate the exact dose of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) required, using a peripheral nerve stimulator device.In the presence of bradycardia, the pulse rate should be increased to about 80/minute with Atropine before administering Neostigmine. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. HOW SUPPLIED Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP 1:1000 (1 mg/mL) NDC 0517-0033-25...............10 mL Multiple Dose Vials.............boxes of 25 Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP 1:2000 (0.5 mg/mL) NDC 0517-0034-25...............10 mL Multiple Dose Vials. ...........boxes of 25 Store at controlled room temperature 15°-30°C (59°-86°F) (See USP). Protect from light.Store in carton until time of use. AMERICAN REGENT LABORATORIES INC., SHIRELY, NY 11967. Rev.9/02. FDA Rev date: n/a

INDICATIONS BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. DOSAGE AND ADMINISTRATION 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 In Adults]. 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 Anticholinergic (Atropine Or Glycopyrrolate) Administration] Dosage In Adults Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using BLOXIVERZ. 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. Prior to administration, visually inspect BLOXIVERZ for particulate matter and discoloration. BLOXIVERZ should be injected slowly by intravenous route over a period of at least 1 minute. 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. 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. 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. 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. 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. 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. HOW SUPPLIED 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 Storage And Handling BLOXIVERZ (Neostigmine Methylsulfate Injection, USP) is available in the following: NDC No. Strength Vial Size 76014-902-10 0.5 mg/mL 10 mL multiple-dose vials (supplied in packages of 10) 76014-903-10 1 mg/mL 10 mL multiple-dose vials (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: Avadel, Avadel Legacy Pharmaceuticals, LLC, Chesterfield, MO 63005. Revised : Jan 2017

PATIENT INFORMATION No information provided. Please refer to the WARNINGS AND PRECAUTIONS sections.

OVERDOSE Overdosage of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) can cause cholinergic crisis, which is characterized by increasing muscle weakness, and through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish from cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) or other drugs in this class, in the presence of cholinergic crisis or of a refractory or "insensitive" state, could have grave consequences.The two types of crises may be differentiated by the use of edrophonium chlorideŠas well as by clinical judgement. Treatment of the two conditions differs radically.Whereas the presence of myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type.The immediate use of Atropine in cholinergic crisis is also recommended. Atropine may also be used to abolish or minimize gastrointestinal side effects or other muscarinic reactions;but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis. The LD50 of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) in mice is 0.3 ± 0.02 mg/kg intravenously, 0.54 ± 0.03 mg/kg subcutaneously and 0.395 ± 0.025 mg/kg intramuscularly; in rats the LD50 is 0.315 ± 0.019 mg/kg intravenously, 0.445 ± 0.032 mg/kg subcutaneously and 0.423 ± 0.032 mg/kg intramuscularly. CONTRAINDICATIONS Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP is contraindicated in patients with known hypersensitivity to the drug. It is also contraindicated in patients with peritonitis or mechanical obstruction of the intestinal or urinary tract.

SIDE EFFECTS Side effects are generally due to an exaggeration of pharmacological effects of which salivation and fasciculation are the most common.Bowel cramps and diarrhea may also occur. The following additional adverse reactions have been reported following the use of either Neostigmine Bromide or Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) . Allergic: Allergic reactions and anaphylaxis. Neurologic: Dizziness, convulsions, loss of consciousness, drowsiness, headache, dysarthria, miosis and visual changes. Cardiovascular: Cardiac arrhythmias (including bradycardia, tachycardia, A-V block and nodal rhythm) and nonspecific EKG changes have been reported, as well as cardiac arrest, syncope and hypotension.These have been predominantly noted following the use of the injectable form of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) . Respiratory: Increased oral, pharyngeal and bronchial secretions, dyspnea, respiratory depression, respiratory arrest and bronchospasm. Dermatologic: Rash and urticaria. Gastrointestinal: Nausea, emesis, flatulence and increased peristalsis. Genitourinary: Urinary frequency. Musculoskeletal: Muscle cramps and spasms, arthralgia. Miscellaneous: Diaphoresis, flushing and weakness. DRUG INTERACTIONS Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP does not antagonize, and may in fact prolong, the Phase 1 block of depolarizing muscle relaxants such as succinylcholine or decamethonium. Certain antibiotics, especially neomycin, streptomycin and kanamycin, have a mild but definite non-depolarizing blocking action which may accentuate neuromuscular block.These antibiotics should be used in the myasthenic patient only where definitely indicated, and then careful adjustment should be made of the anticholinesterase dosage. Local and some general anesthetics, antiarrhythmic agents and other drugs that interfere with neuromuscular transmission should be used cautiously, if at all, in patients with myasthenia gravis;the dose of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) may have to be increased accordingly.

SIDE EFFECTS 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 Post 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 DRUG INTERACTIONS 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.

WARNINGS Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP should be used with caution in patients with epilepsy, bronchial asthma, bradycardia, recent coronary occlusion, vagotonia, hyperthyroidism, cardiac arrhythmias or peptic ulcer.When large doses of Neostigmine are administered, the prior or simultaneous injection of Atropine Sulfate may be advisable.Separate syringes should be used for the Neostigmine and Atropine.Because of the possibility of hypersensitivity in an occasional patient, Atropine and anti-shock medication should always be readily available. PRECAUTIONS General It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) .Both conditions result in extreme muscle weakness but require radically different treatment (see OVERDOSE). Carcinogenesis, Mutagenesis and Impairment of Fertility There have been no studies with Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) which would permit an evaluation of its carcinogenic or mutagenic potential. Studies on the effect of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) on fertility and reproduction have not been performed. Pregnancy Teratogenic Effects Pregnancy Category C.There are no adequate or well-controlled studies of Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) in either laboratory animals or in pregnant women.It is not known whether Neostigmine can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) Injection, USP should be given to a pregnant woman only if clearly needed. Nonteratogenic Effects Anticholinesterase drugs may cause uterine irritability and induce premature labor when given intravenously to pregnant women near term. Nursing Mothers It is not known whether Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) is excreted in human milk.Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Neostigmine Methylsulfate (neostigmine methylsulfate (neostigmine methylsulfate injection) injection) in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in children have not been established.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS 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]. 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. Hypersensitivity Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available. 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. 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]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility 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). Use In Specific Populations Pregnancy Risk Summary There are no adequate or well-controlled studies of BLOXIVERZ in pregnant women. It is not known whether BLOXIVERZ can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. The incidence of malformations in human pregnancies has not been established for neostigmine as the data are limited. All pregnancies, regardless of drug exposure, have a background risk of 2 to 4% for major birth defects, and 15 to 20% for pregnancy loss. No adverse effects were noted in rats or rabbits treated with human equivalent doses of neostigmine methylsulfate doses up to 8.1 and 13 mcg/kg/day, respectively, during organogenesis (0.1 to 0.2-times the maximum recommended human dose of 5 mg/60 kg person/day based on body surface area comparisons). Anticholinesterase drugs, including neostigmine may cause uterine irritability and induce premature labor when administered to pregnant women near term. BLOXIVERZ should be given to a pregnant woman only if clearly needed. Data Animal Data In embryofetal development studies, rats and rabbits were administered neostigmine methylsulfate at human equivalent doses (HED, on a mg/m² 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/m² 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. Labor And Delivery The effect of BLOXIVERZ on the mother and fetus with regard to labor, delivery, the need for forceps delivery or other intervention or resuscitation of the newborn, is not known. Cholinesterase inhibitor drugs may induce premature labor when given intravenously to pregnant women near term. Nursing Mothers It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when BLOXIVERZ is administered to a nursing woman. Pediatric Use 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]. 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. Geriatric Use 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]. Renal Impairment 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. Hepatic Impairment 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.