PREVDUO

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.

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.

<table cellspacing="0" cellpadding="0" border="0" width="714"><colgroup><col width="46.4335664335664%"/><col width="53.5664335664336%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold">S</content><content styleCode="bold">y</content><content styleCode="bold">s</content><content styleCode="bold">t</content><content styleCode="bold">e</content><content styleCode="bold">m Organ Class</content> </td><td styleCode="Rrule" valign="top"><content styleCode="bold">Adverse Reaction</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Cardiovascular Disorders</content> </td><td styleCode="Rrule" valign="middle">bradycardia, hypotension, tachycardia/heart rate increase </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Gastrointestinal Disorders</content> </td><td styleCode="Rrule" valign="middle">dry mouth, nausea, post-procedural nausea, vomiting </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">General Disorders and Administration Site Conditions</content> </td><td styleCode="Rrule" align="justify" valign="middle">incision site complication, pharyngolaryngeal pain, procedural complication, procedural pain </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Nervous System Disorders</content> </td><td styleCode="Rrule" align="justify" valign="middle">dizziness, headache, postoperative shivering, prolonged neuromuscular blockade </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Psychiatric Disorders</content> </td><td styleCode="Rrule" valign="middle">Insomnia </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content> </td><td styleCode="Rrule" valign="middle">dyspnea, oxygen desaturation &lt; 90% </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </td><td styleCode="Rrule" valign="middle">Pruritus </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="942.97"><colgroup><col width="46.4033850493653%"/><col width="53.5966149506347%"/></colgroup><thead><tr><th styleCode="Lrule Rrule Toprule"><content styleCode="bold">S</content><content styleCode="bold">y</content><content styleCode="bold">s</content><content styleCode="bold">t</content><content styleCode="bold">e</content><content styleCode="bold">m Organ Class</content> </th><th styleCode="Lrule Rrule Toprule"><content styleCode="bold">Adverse Reaction</content> </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Allergic Disorders</content> </td><td styleCode="Rrule" valign="middle">allergic reactions, anaphylaxis </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Nervous System Disorders</content> </td><td styleCode="Rrule" align="justify" valign="middle">convulsions, drowsiness, dysarthria, fasciculation, loss of consciousness, miosis, visual changes </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Cardiovascular Disorders</content> </td><td styleCode="Rrule" valign="middle">cardiac arrest, cardiac arrhythmias (A-V block, nodal rhythm), hypotension, nonspecific EKG changes, syncope </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content> </td><td styleCode="Rrule" align="justify" valign="middle">bronchospasm; increased oral, pharyngeal and bronchial secretions; respiratory arrest; respiratory depression </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Skin and Sub-cutaneous Tissue Disorders</content> </td><td styleCode="Rrule" valign="middle">rash, urticaria </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Gastrointestinal Disorders</content> </td><td styleCode="Rrule" valign="middle">bowel cramps, diarrhea, flatulence, increased peristalsis </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Renal and Urinary Disorders</content> </td><td styleCode="Rrule" valign="middle">urinary frequency </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content> </td><td styleCode="Rrule" valign="middle">arthralgia, muscle cramps, spasms, weakness </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Miscellaneous</content> </td><td styleCode="Rrule" valign="middle">diaphoresis, flushing </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="942.97"><colgroup><col width="46.6854724964739%"/><col width="53.3145275035261%"/></colgroup><thead><tr><th styleCode="Lrule Rrule Toprule"><content styleCode="bold">S</content><content styleCode="bold">y</content><content styleCode="bold">s</content><content styleCode="bold">t</content><content styleCode="bold">e</content><content styleCode="bold">m Organ Class</content> </th><th styleCode="Lrule Rrule Toprule"><content styleCode="bold">Adverse Reaction</content> </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Cardiovascular Disorders</content> </td><td styleCode="Rrule" align="justify" valign="middle">cardiac arrhythmias (including bradycardia, ventricular tachycardia, ventricular fibrillation), cardiac arrest, hypertension, hypotension, heart block and QTc interval prolongation </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content> </td><td styleCode="Rrule" valign="middle">respiratory arrest </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Injection site reactions</content> </td><td styleCode="Rrule" valign="middle">pruritus, edema, erythema, and pain at injection site </td></tr><tr><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Miscellaneous</content> </td><td styleCode="Rrule" valign="middle">malignant hyperthermia </td></tr></tbody></table>