PREVDUO

1 INDICATIONS AND USAGE PREVDUO ® , a fixed dose combination of cholinesterase inhibitor and antimuscarinic agent, is indicated in patients age two years and above for the reversal of the effects of nondepolarizing neuromuscular blocking agents (NMBA) after surgery, while decreasing the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) associated with cholinesterase inhibition following NMBA reversal administration. PREVDUO ® , a fixed dose combination of a cholinesterase inhibitor and antimuscarinic agent, is indicated in patients age two years and above for the reversal of the effects of non-depolarizing neuromuscular blocking agents (NMBAs) after surgery, while decreasing the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) associated with cholinesterase inhibition following NMBA reversal administration ( 1 ).

2 DOSAGE AND ADMINISTRATION • Should be administered by trained healthcare providers ( 2.1 ) • Peripheral nerve stimulator and monitoring for twitch responses should be used to determine when PREVDUO ® should be initiated and if additional doses are needed ( 2.2 ) • For reversal of NMBAs with shorter half-lives in patients age 2 years and up, when first twitch response is substantially greater than 10% of baseline, or when a second twitch is present: 0.03 mg/kg of neostigmine methylsulfate (0.006 mg/kg of glycopyrrolate) by intravenous route ( 2.2 ) • For reversal of NMBAs with longer half-lives or when first twitch response is close to 10% of baseline in patients age 2 years and up: 0.07 mg/kg of neostigmine methylsulfate (0.014 mg/kg of glycopyrrolate) by intravenous route ( 2.2 ) • Maximum total dosage is 0.07 mg/kg of neostigmine methylsulfate or up to a total of 5 mg neostigmine methylsulfate (whichever is less) ( 2.2 ) 2.1 Important Dosage and Administration Information • PREVDUO ® 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 PREVDUO ® should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of PREVDUO ® and should be used to determine the need for additional doses. • PREVDUO ® is for intravenous use only and should be injected slowly over a period of at least 1 minute. The PREVDUO ® dosage is weight-based [ see Dosage and Administration ( 2.2 ) ]. • Prior to PREVDUO ® 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. • Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using PREVDUO ® . • 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 PREVDUO ® . • Prior to administration, visually inspect PREVDUO ® for particulate matter and discoloration. • 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 PREVDUO ® . • 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. 2.2 Dosage in Adults A 0.03 mg/kg to 0.07 mg/kg dose of Neostigmine methylsulfate (0.006 mg/kg to 0.014 mg/kg dose of Glycopyrrolate) Injection will generally achieve a TOF twitch ratio of 90% (TOF 0.9 ) within 10 to 20 minutes of administration, with minimization of neostigmine-induced bradycardia due to the included 0.2 mg of glycopyrrolate per 1 mg neostigmine. 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 of neostigmine methylsulfate (0.006 mg/kg of glycopyrrolate) 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 of neostigmine methylsulfate (0.014 mg/kg of glycopyrrolate) dose is recommended for: • Reversal of 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 The recommended maximum total dose is 0.07 mg/kg of neostigmine methylsulfate or up to a total of 5 mg of neostigmine methylsulfate, whichever is less. 2.3 Dosage in Pediatric Patients age 2 years and above For pediatric population age >2 years, adult guidelines should be followed when PREVDUO ® is administered. Pediatric patients require PREVDUO ® doses similar to those for adult patients. PREVDUO ® is not recommended for use in pediatric patients less than 2 years of age, as the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate [ see Use in Specific Populations ( 8.4 ) ]. 2.4 Instructions for Use (Administration Technique) a) Inspect the outer carton for: - absence of external particles - drug product name - dosage form - drug strength - fill volume - route of administration - expiration date b) Take out the plastic tray from the outer carton and remove the prefilled syringe from tray. c) Perform visual inspection of the prefilled syringe for: - absence of physical damage to syringe - absence of external particles - absence of internal particles (particulate matter) - discoloration - drug product name - drug strength - fill volume - expiration date d) Remove tip cap by twisting off e) Discard the tip cap. f) Expel the air bubble by pushing the plunger rod. Adjust the dose (if applicable). g) Connect the prefilled syringe to an appropriate intravenous connection. Ensure that the prefilled syringe is securely attached to the needle or needleless luer access device (NLAD). h) Press the plunger rod slowly to deliver the medication through needle or needleless luer access device (NLAD) over a period of at least 1 minute. Ensure that appropriate pressure is maintained on the plunger rod during the entire administration. i) Remove the prefilled syringe from needle or needleless luer access device (NLAD) and discard into appropriate receptacle. When needle is connected to syringe, to prevent needle-stick injuries, needles should not be recapped. NOTES: - All steps given in the ‘instructions for use’ must be performed sequentially - Do not re-sterilize the 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 use only ifu-1 IFU-2 IFU-3

4 CONTRAINDICATIONS PREVDUO ® 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) and glycopyrrolate or any inactive ingredients [ see Warnings and Precautions ( 5.3 ) ]. • peritonitis or mechanical obstruction of the intestinal or urinary tract. • Glaucoma; obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis, etc.); paralytic ileus, intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis. • Hypersensitivity to neostigmine, glycopyrrolate, or nonactive ingredients ( 4 ) • Peritonitis or mechanical obstruction of the intestinal or urinary tract ( 4 ) • Patients with glaucoma; obstructive uropathy; obstructive disease of the gastrointestinal tract; paralytic ileus, intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis ( 4 ).

5 WARNINGS AND PRECAUTIONS • Bradycardia : consideration should be given to administration of glycopyrrolate prior to neostigmine (i.e., as separate products) in patients with bradycardia or in patients in whom bradycardia, a known risk of neostigmine methysulfate, may cause hemodynamic instability. ( 5.1 ) • Serious Reactions with Coexisting Conditions : Use with caution in patients with, coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome, hyperthyroidism or myasthenia gravis. ( 5.2 ) • Hypersensitivity : Because of the possibility of hypersensitivity, medications to treat anaphylaxis should be readily available. ( 5.3 ) • Neuromuscular Dysfunction : Can occur if large doses of PREVDUO ® are administered when neuromuscular blockade is minimal; reduce dose if recovery from neuromuscular blockade is nearly complete. ( 5.4 ) • Cholinergic Crisis : It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of neostigmine. ( 5.5 ) • Precipitation of Acute Glaucoma : Glycopyrrolate may cause mydriasis and increase intraocular pressure in patients with glaucoma. Advise patients with glaucoma to promptly seek medical care if they experience symptoms of acute angle closure glaucoma. ( 5.6 ) • Drowsiness and Blurred Vision : Warn patients about participating in activities requiring mental alertness. ( 5.7 ) • Heat Prostration : Advise patients to avoid exertion and high environmental temperatures after receiving PREVDUO ® . ( 5.8 ) • Intestinal Obstruction : Diarrhea may be an early symptom of incomplete intestinal obstruction. Avoid use in patients with diarrhea and ileostomy or colostomy. ( 5.9 ) • Tachycardia : Increase in heart rate may occur. Use with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, hypertension, or hyperthyroidism. ( 5.10 ) 5.1 Bradycardia Neostigmine, a component of PREVDUO ® , is associated with bradycardia. Consideration should be given to administration of glycopyrrolate prior to neostigmine (i.e., as separate products) in patients with bradycardia or in patients in whom bradycardia, a known risk of neostigmine methysulfate, may cause hemodynamic instability. 5.2 Serious Adverse Reactions in Patients with Certain Coexisting Conditions PREVDUO ® should be used with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, recent acute coronary syndrome, hypertension, myasthenia gravis and hyperthyroidism. 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 acute 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. 5.3 Hypersensitivity Because of the possibility of hypersensitivity, medications to treat anaphylaxis should be readily available. 5.4 Neuromuscular Dysfunction Large doses of PREVDUO ® administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of PREVDUO ® 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. Both conditions result in extreme muscle weakness but require radically different treatment. [ see Overdosage ( 10 ) ]. 5.6 Precipitation of Acute Glaucoma Glycopyrrolate, a component of PREVDUO ® , is contraindicated in patients with glaucoma because it may cause mydriasis and increase intraocular pressure. Advise patients with glaucoma to promptly seek medical care in the event that they experience symptoms of acute angle closure glaucoma (pain and reddening of the eyes, accompanied by dilated pupils). 5.7 Drowsiness and Blurred Vision Glycopyrrolate, a component of PREVDUO ® , may cause drowsiness or blurred vision. Warn patients not to participate in activities requiring mental alertness, such as operate a motor vehicle or other machinery or perform hazardous work until these issues resolve. 5.8 Heat Prostration Glycopyrrolate, a component of PREVDUO ® , may cause heat prostration (due to decreased sweating) in presence of fever, high environmental temperature, and/or during physical exercise, particularly in children and the elderly. Advise patients to avoid exertion and high environmental temperature after receiving PREVDUO ® . 5.9 Intestinal Obstruction Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with Glycopyrrolate, a component of PREVDUO ® is inappropriate and possibly harmful. Avoid use in patients with these conditions. 5.10 Tachycardia Investigate any tachycardia before giving Glycopyrrolate, a component of PREVDUO ® because an increase in the heart rate may occur. Use with caution in patients with coronary artery disease, congestive heart failure, cardiac arrhythmias, hypertension, or hyperthyroidism.

7 DRUG INTERACTIONS Neostigmine Methylsulfate 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 with other drugs which may alter the activity of metabolizing enzymes or transporters. Glycopyrrolate The concurrent use of glycopyrrolate with other anticholinergics or medications with anticholinergic activity, such as phenothiazines, antiparkinson drugs, or tricyclic antidepressants, may intensify the antimuscarinic effects and may result in an increase in anticholinergic side effects. The concurrent use of glycopyrrolate with other anticholinergics or medications with anticholinergic activity may intensify the antimuscarinic effects and may result in an increase in anticholinergic side effects. ( 7 )

6 ADVERSE REACTIONS • Most common adverse reactions to neostigmine during treatment: bradycardia, nausea, vomiting, blurred vision and photophobia. ( 6 ) • Most common adverse reactions to glycopyrrolate are related to anticholinergic pharmacology and may include xerostomia (dry mouth); urinary hesitancy and retention; blurred vision and photophobia due to mydriasis (dilation of the pupil); cycloplegia; increased ocular tension; tachycardia; bradycardia; palpitation; and decreased sweating. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Endo at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Neostigmine Methylsulfate 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 addition of glycopyrrolate to the neostigmine-glycopyrrolate prefilled syringe 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 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 Glycopyrrolate 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. Anticholinergics, including glycopyrrolate, can produce certain effects, most of which are extensions of their pharmacologic actions. Adverse reactions may include xerostomia (dry mouth); urinary hesitancy and retention; blurred vision and photophobia due to mydriasis (dilation of the pupil); cycloplegia; increased ocular tension; tachycardia; palpitation; decreased sweating; loss of taste; headache; nervousness; drowsiness; weakness; dizziness; insomnia; nausea; vomiting; impotence; suppression of lactation; constipation; bloated feeling; severe allergic reactions including anaphylactic/anaphylactoid reactions; hypersensitivity; urticaria, pruritus, dry skin, and other dermal manifestations; some degree of mental confusion and/or excitement, especially in elderly persons. 6.2 Post Marketing Experience Neostigmine Methylsulfate The following adverse reactions have been identified during post-approval 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. S y s t e m 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 Glycopyrrolate The following adverse events have been identified during post-approval use of glycopyrrolate. 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: S y s t e m Organ Class Adverse Reaction Cardiovascular Disorders cardiac arrhythmias (including bradycardia, ventricular tachycardia, ventricular fibrillation), cardiac arrest, hypertension, hypotension, heart block and QTc interval prolongation Respiratory, Thoracic and Mediastinal Disorders respiratory arrest Injection site reactions pruritus, edema, erythema, and pain at injection site Miscellaneous malignant hyperthermia Glycopyrrolate is chemically a quaternary ammonium compound; hence, its passage across lipid membranes, such as the blood-brain barrier is limited. For this reason, the occurrence of CNS-related side effects is lower, in comparison to their incidence following administration of anticholinergics which are chemically tertiary amines that can cross this barrier readily.

8.1 Pregnancy Risk Summary Neostigmine Methylsulfate There are no adequate or well-controlled studies of neostigmine in pregnant women. It is not known whether neostigmine 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. Glycopyrrolate Limited data available with glycopyrrolate use during pregnancy have not identified a drug-associated risk of birth defects and miscarriage, however, most of the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of Cesarean-section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores (see Data). In animal reproduction studies in pregnant rats and rabbits administered glycopyrrolate orally (rats) and intramuscularly (rabbits) during the period of organogenesis, no teratogenic effects were seen at 640-times and 10-times the maximum recommended human dose (MRHD) of 1 mg (on a mg/m 2 basis), respectively (see Data). The estimated background risk for 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 2-4% and 15-20%, respectively. PREVDUO @ should be only given to a pregnant woman if the benefit outweighs the risk. Data Human Data Neostigmine Methylsulfate: There are no adequate or well-controlled studies of neostigmine methylsulfate in pregnant women. Glycopyrrolate: Published, randomized, controlled trials over several decades, which compared the use of glycopyrrolate to another antimuscarinic agent in pregnant women during Cesarean section, have not identified adverse maternal or infant outcomes. In normal doses (0.004 mg/kg), glycopyrrolate does not appear to affect fetal heart rate or fetal heart rate variability to a significant degree. Concentrations of glycopyrrolate in umbilical venous and arterial blood and in the amniotic fluid are low after intramuscular administration to parturients. Therefore, glycopyrrolate does not appear to penetrate through the placental barrier in significant amounts. There are no studies on the safety of glycopyrrolate exposure during the period of organogenesis, and therefore, it is not possible to draw any conclusions on the risk of birth defects following exposure to glycopyrrolate during pregnancy. In addition, there are no data on the risk of miscarriage following fetal exposure to glycopyrrolate. Animal Data Neostigmine Methylsulfate: 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 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 maximum recommended daily human dose (MRHD) of 5 mL/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. Glycopyrrolate: Reproduction studies with glycopyrrolate were performed in rats at a dietary dose of approximately 65 mg/kg/day (exposure was approximately 640 times the MRHD of 1 mg on a mg/m 2 basis) and rabbits at intramuscular doses of up to 0.5 mg/kg/day (exposure was approximately 10 times the maximum recommended daily human dose on a mg/m 2 basis). These studies produced no teratogenic effects to the fetus. A preclinical study on reproductive performance of rats given glycopyrrolate resulted in a decreased rate of conception and survival at weaning.