Neostigmine Methylsulfate

1. INDICATIONS AND USAGE Neostigmine Methylsulfate Injection, USP is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. Neostigmine Methylsulfate Injection, USP, a cholinesterase inhibitor, is indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery. ( 1 )

2. DOSAGE AND ADMINISTRATION Neostigmine Methylsulfate Injection, USP is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. Should be administered by trained healthcare providers ( 2.1 ) Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when Neostigmine Methylsulfate Injection, USP should be initiated and if additional doses are needed ( 2.2 ) 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 ) 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 Neostigmine Methylsulfate Injection, USP ( 2.4 ) 2.1. Important Dosage Information Neostigmine Methylsulfate Injection, USP 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 Neostigmine Methylsulfate Injection, USP should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of Neostigmine Methylsulfate Injection, USP and should be used to determine the need for additional doses. Neostigmine Methylsulfate Injection, USP is for intravenous use only and should be injected slowly over a period of at least 1 minute. The Neostigmine Methylsulfate Injection, USP dosage is weight-based [see Dosage and Administration ( 2.2 )] . Prior to Neostigmine Methylsulfate Injection, USP 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 Neostigmine Methylsulfate Injection, USP [see Dosage and Administration ( 2.4 )]. 2.2. Dosage in Adults a. Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using Neostigmine Methylsulfate Injection, USP. 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 Neostigmine Methylsulfate Injection, USP. c. Prior to administration, visually inspect Neostigmine Methylsulfate Injection, USP for particulate matter and discoloration. d. Neostigmine Methylsulfate Injection, USP 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 Neostigmine Methylsulfate Injection, USP 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. f. TOF m …

3 DOSAGE FORMS AND STRENGTHS Neostigmine methylsulfate injection, USP is a clear, colorless, sterile, nonpyrogenic solution intended for intravenous use. Neostigmine methylsulfate injection, USP is available as: Injection: 0.5 mg/mL, 5 mg of neostigmine methylsulfate, USP in 10 mL multiple-dose vials. Injection: 1 mg/mL, 10 mg of neostigmine methylsulfate, USP in 10 mL multiple-dose vials. Injection: 0.5 mg/mL and 1 mg/mL in 10 mL multiple-dose vials. ( 3 )

4 CONTRAINDICATIONS Neostigmine Methylsulfate Injection, USP, 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). with 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 )

6 ADVERSE REACTIONS Most common adverse reactions during treatment: bradycardia, nausea and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc . at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. S y s t e m Organ Class Adverse Reaction Cardiovascular Disorders bradycardia, hypotension, tachycardia/heart rate increase Gastrointestinal Disorders dry mouth, nausea, post‐procedural nausea, vomiting Gen e r a l 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 6.2 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 ‐ c u taneous 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

7 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 Neostigmine Methylsulfate Injection, USP, with other drugs which may alter the activity of metabolizing enzymes or transporters.

8 USE IN SPECIFIC POPULATIONS Pregnancy: No human data and limited animal data exist. Use only if clearly needed. 8.1. Pregnancy Risk Summary There are no adequate or well-controlled studies of Neostigmine Methylsulfate Injection, USP, in pregnant women. It is not known whether Neostigmine Methylsulfate Injection, USP, 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. Neostigmine Methylsulfate Injection, USP, 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/m 2 basis) of 1.6, 4 and 8.1 mcg/kg/day 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 occurred at HED doses up 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. 8.2. Labor and Delivery The effect of Neostigmine Methylsulfate Injection, USP, 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. 8.3. Nursing Mothers It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when Neostigmine Methylsulfate Injection, USP, is administered to a nursing woman. 8.4. Pediatric Use Neostigmine Methylsulfate Injection, USP, 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 Neostigmine Methylsulfate Injection, USP, (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less). The dose of Neostigmine Methylsulfate Injection, USP, required to reverse neuromuscular blockade in children varies between 0.03 mg and 0.07 mg …

12.1. 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 non-depolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade.

11 DESCRIPTION Neostigmine methylsulfate, a cholinesterase inhibitor, is ( m -hydroxyphenyl) trimethyl ammonium methylsulfate dimethylcarbamate. The structural formula is: Neostigmine methylsulfate, USP is a white or almost white, crystalline powder (or) colorless crystals and is very soluble in water and soluble in alcohol. Neostigmine methylsulfate injection, USP is a sterile, nonpyrogenic clear colorless solution intended for intravenous use. Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate 0.5 mg, phenol (as liquefied 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 glacial 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 (as liquefied 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 glacial acetic acid/sodium hydroxide to achieve a value of 5.5. Chemical Structure

10 OVERDOSAGE Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of Neostigmine Methylsulfate Injection, USP (cholinergic crisis), but may be managed by the use of additional atropine or glycopyrrolate. The possibility of iatrogenic overdose can be lessened by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored. Overdosage of Neostigmine Methylsulfate Injection, USP, 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 Injection, USP, 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 chloride as well as by clinical judgment. 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 lessen gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.

16 HOW SUPPLIED SECTION Neostigmine Methylsulfate Injection, USP is a clear, colorless solution and is available in multi -dose USP Type-I clear glass tubular vials in the following package sizes: NDC No. Strength Vial Size 70700-171-23 0.5 mg/mL 10 mL multiple-dose vial packaged in a carton containing 10 vials (Supplied in packages of 10) 70700-172-23 1 mg/mL 10 mL multiple-dose vial packaged in a carton containing 10 vials (Supplied in packages of 10) 70700-171-22 0.5 mg/mL 10 mL multiple-dose vial packaged in a carton containing 10 vials (Supplied in packages of 1) 70700-172-22 1 mg/mL 10 mL multiple-dose vial packaged in a carton containing 10 vials (Supplied in packages of 1) The vial stopper is not made with natural rubber latex. Neostigmine Methylsulfate Injection, USP 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: Xiromed, LLC, Florham Park, NJ 07932 Product of India October 2021 PI-172-00 LEA-020363-00