Neostigmine methylsulfate

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

2 DOSAGE & ADMINISTRATION • 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 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 (2.4) 2.1. Important Dosage Information Neostigmine Methylsulfate Injection 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 should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of Neostigmine Methylsulfate Injection and should be used to determine the need for additional doses. Neostigmine Methylsulfate Injection is for intravenous use only and should be injected slowly over a period of at least 1 minute. The Neostigmine Methylsulfate Injection dosage is weight-based [see Dosage and Administration (2.2)]. Prior to Neostigmine Methylsulfate Injection 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 [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. 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. c. Prior to administration, visually inspect Neostigmine Methylsulfate Injection for particulate matter and discoloration. d. Neostigmine Methylsulfate Injection 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 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: i. Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or ii. 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 iii. NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or iv. When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or v. 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 Neostigmine Methylsulfate Injection. g. TOF monitoring alone should not be relied upon to determine …

5 WARNINGS AND PRECAUTIONS • Bradycardia: Atropine or glycopyrrolate should be administered prior to Neostigmine Methylsulfate Injection 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 Neostigmine Methylsulfate Injection are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. (5.4) 5.1. Bradycardia Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to Neostigmine Methylsulfate Injection to lessen the risk of bradycardia [ see Dosage and Administration (2.4)] . 5.2. Serious Adverse Reactions in Patients with Certain Coexisting Conditions Neostigmine Methylsulfate Injection 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 asbradycardia, 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. 5.3. Hypersensitivity Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available. 5.4. Neuromuscular Dysfunction Large doses of Neostigmine Methylsulfate Injection administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of Neostigmine Methylsulfate Injection should be reduced if recovery from neuromuscular blockade is nearly complete. 5.5. Cholinergic Crisis It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of Neostigmine Methylsulfate Injection. Both conditions result in extreme muscle weakness but require radically different treatment. [see Overdosage (10)]

4 CONTRAINDICATIONS Neostigmine Methylsulfate Injection 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)

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

8.1 Pregnancy Risk Summary There are no adequate or well-controlled studies of Neostigmine Methylsulfate Injection in pregnant women. It is not known whether Neostigmine Methylsulfate Injection 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 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.

8.3 Nursing Mothers It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when Neostigmine Methylsulfate Injection is administered to a nursing woman.

6 ADVERSE REACTIONS Most common adverse reactions during treatment: bradycardia, nausea and vomiting. (6) To report SUSPECTED ADVERSE REACTIONS, contact XIROMED LLC at 1-844-XIROMED (844-947-6633) 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. 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 6.2. 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-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