Adenosine

5 WARNINGS AND PRECAUTIONS Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction . Fatal cardiac events have occurred. Avoid use in patients with symptoms or signs of acute myocardial ischemia. Appropriate resuscitative measures should be available ( 5.1 ) Sinoatrial (SA) and Atrioventricular (AV) Nodal Block . First-, second- or third-degree AV block, or sinus bradycardia can occur. Discontinue adenosine if patient develops persistent or symptomatic high-grade AV block ( 5.2 ) Bronchoconstriction . Can induce dyspnea, bronchoconstriction, and respiratory compromise, especially in patients with obstructive pulmonary disease. Discontinue adenosine if patient develops severe respiratory difficulties ( 5.3 ) Hypotension . Significant hypotension can occur. Discontinue adenosine if patient develops persistent or symptomatic hypotension ( 5.4 ) Cerebrovascular Accidents . Hemorrhagic and ischemic cerebrovascular accidents have occurred ( 5.5 ) Seizures . New onset or recurrence of convulsive seizures have occurred. Use of methylxanthines (e.g., caffeine, aminophylline and theophylline) is not recommended in patients who experience seizures in association with adenosine ( 5.6 ) Hypersensitivity . Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Have personnel and resuscitative equipment immediately available ( 5.7 ) Atrial Fibrillation . Reported in patients with or without a history of atrial fibrillation ( 5.8 ) Hypertension . Clinically significant increases in systolic and diastolic pressure have been observed ( 5.9 ) 5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following adenosine infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to adenosine. Appropriate resuscitative measures should be available [see Overdosage ( 10 )] . 5.2 Sinoatrial and Atrioventricular Nodal Block Adenosine exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following adenosine administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) [see Clinical Trials Experience ( 6.1 )] . Use adenosine with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue adenosine in any patient who develops persistent or symptomatic high-grade AV block. 5.3 Bronchoconstriction Adenosine administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue adenosine in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to adenosine administration [see Clinical Trials Experience ( 6.1 ), Overdosage ( 10 ), and Clinical Pharmacology ( 12.2 )]. 5.4 Hypotension Adenosine is a potent peripheral vasodilator and can induce significant hypotension. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. Discontinue adenosine in any patient who develops persistent or symptomatic hypotension. 5.5 Cerebrovascular Accident Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of adenosine including hypotension or hypertension can be associated with these adverse reactions [see Warnings and Precautions ( 5.4 ) and ( 5.9 )] . 5.6 Seizures New-onset or recurrence of convulsive seizures has occurred following adenosine. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with adenosine. Methylxanthine use is not recommended in patients who experience seizures in association with adenosine administration [see Overdosage ( 10 )]. 5.7 Hypersensitivity, including Anaphylaxis Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Symptomatic treatment may be required. Have personnel and appropriate treatment available. Resuscitative measures may be necessary if symptoms progress [see Post-Marketing Experience ( 6.2 )]. 5.8 Atrial Fibrillation Adenosine can cause atrial fibrillation in patients with or without a history of atrial fibrillation. Atrial fibrillation typically began 1.5 to 3 minutes after initiation of adenosine, lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm [see Post-Marketing Experience ( 6.2 )] . 5.9 Hypertension Adenosine can induce clinically significant increases in systolic and diastolic blood pressure. Most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours [see Clinical Trials Experience ( 6.1 )] .

5.1 Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction Fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following adenosine infusion. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to adenosine. Appropriate resuscitative measures should be available [see Overdosage ( 10 )] .

5.2 Sinoatrial and Atrioventricular Nodal Block Adenosine exerts a direct depressant effect on the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia. In clinical trials, approximately 6% of patients developed AV block following adenosine administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) [see Clinical Trials Experience ( 6.1 )] . Use adenosine with caution in patients with pre-existing first-degree AV block or bundle branch block. Do not use in patients with high-grade AV block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). Discontinue adenosine in any patient who develops persistent or symptomatic high-grade AV block.

5.3 Bronchoconstriction Adenosine administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). Do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). Discontinue adenosine in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to adenosine administration [see Clinical Trials Experience ( 6.1 ), Overdosage ( 10 ), and Clinical Pharmacology ( 12.2 )].

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: Fatal Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction [see Warnings and Precautions ( 5.1 )] Sinoatrial and Atrioventricular Nodal Block [see Warnings and Precautions ( 5.2 )] Bronchoconstriction [see Warnings and Precautions ( 5.3 )] Hypotension [see Warnings and Precautions ( 5.4 )] Cerebrovascular Accident [see Warnings and Precautions ( 5.5 )] Seizures [see Warnings and Precautions ( 5.6 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] Atrial fibrillation [see Warnings and Precautions ( 5.8 )] Hypertension [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥ 10%) are: flushing; chest discomfort; shortness of breath; headache; throat, neck or jaw discomfort; gastrointestinal discomfort; and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi, LLC at 1-800-551-7176 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. The following adverse reactions, with an incidence of at least 1%, were reported with adenosine among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after adenosine administration. 8% of the adverse reactions began with adenosine infusion and persisted for up to 24 hours. The most common (incidence ≥ 10%) adverse reactions to adenosine are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2). Table 2. Adverse Reactions in Clinical Trials (Frequency ≥ 1%) Adverse Reactions Adenosine N=1,421 Flushing 44% Chest discomfort 40% Dyspnea 28% Headache 18% Throat, neck or jaw discomfort 15% Gastrointestinal discomfort 13% Lightheadedness/dizziness 12% Upper extremity discomfort 4% ST segment depression 3% First-degree AV block 3% Second-degree AV block 3% Paresthesia 2% Hypotension 2% Nervousness 2% Arrhythmias 1% Adverse reactions to adenosine of any severity reported in less than 1% of patients include: Body as a Whole: back discomfort, lower extremity discomfort, weakness Cardiovascular System: myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure > 200 mm Hg) Respiratory System: cough Central Nervous System: drowsiness, emotional instability, tremors Genital/Urinary System: vaginal pressure, urgency Special Senses: blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort 6.2 Post-Marketing Experience The following adverse reactions have been reported from marketing experience with adenosine. Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: cardiac arrest, atrial fibrillation, cardiac failure, myocardial infarction, tachycardia, ventricular arrhythmia Gastrointestinal Disorders: nausea and vomiting General Disorders and Administration Site Conditions: chest pain, injection site reaction, infusion site pain Immune System Disorders: hypersensitivity Nervous System Disorders: cerebrovascular accident including intracranial hemorrhage, seizure activity including tonic-clonic (grand mal) seizures, loss of consciousness Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, respiratory arrest, throat tightness

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. The following adverse reactions, with an incidence of at least 1%, were reported with adenosine among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after adenosine administration. 8% of the adverse reactions began with adenosine infusion and persisted for up to 24 hours. The most common (incidence ≥ 10%) adverse reactions to adenosine are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2). Table 2. Adverse Reactions in Clinical Trials (Frequency ≥ 1%) Adverse Reactions Adenosine N=1,421 Flushing 44% Chest discomfort 40% Dyspnea 28% Headache 18% Throat, neck or jaw discomfort 15% Gastrointestinal discomfort 13% Lightheadedness/dizziness 12% Upper extremity discomfort 4% ST segment depression 3% First-degree AV block 3% Second-degree AV block 3% Paresthesia 2% Hypotension 2% Nervousness 2% Arrhythmias 1% Adverse reactions to adenosine of any severity reported in less than 1% of patients include: Body as a Whole: back discomfort, lower extremity discomfort, weakness Cardiovascular System: myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure > 200 mm Hg) Respiratory System: cough Central Nervous System: drowsiness, emotional instability, tremors Genital/Urinary System: vaginal pressure, urgency Special Senses: blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort

6.2 Post-Marketing Experience The following adverse reactions have been reported from marketing experience with adenosine. Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: cardiac arrest, atrial fibrillation, cardiac failure, myocardial infarction, tachycardia, ventricular arrhythmia Gastrointestinal Disorders: nausea and vomiting General Disorders and Administration Site Conditions: chest pain, injection site reaction, infusion site pain Immune System Disorders: hypersensitivity Nervous System Disorders: cerebrovascular accident including intracranial hemorrhage, seizure activity including tonic-clonic (grand mal) seizures, loss of consciousness Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, respiratory arrest, throat tightness

<table cellspacing="0" cellpadding="0" border="0" width="437"><tbody><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule" align="center"><content styleCode="bold">Adverse Reactions</content> </td><td valign="top" styleCode="Rrule" align="center"><content styleCode="bold">Adenosine</content> <content styleCode="bold">N=1,421</content> </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Flushing </td><td valign="top" styleCode="Rrule" align="center">44% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Chest discomfort </td><td valign="top" styleCode="Rrule" align="center">40% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Dyspnea </td><td valign="top" styleCode="Rrule" align="center">28% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Headache </td><td valign="top" styleCode="Rrule" align="center">18% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Throat, neck or jaw discomfort </td><td valign="top" styleCode="Rrule" align="center">15% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Gastrointestinal discomfort </td><td valign="top" styleCode="Rrule" align="center">13% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Lightheadedness/dizziness </td><td valign="top" styleCode="Rrule" align="center">12% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Upper extremity discomfort </td><td valign="top" styleCode="Rrule" align="center">4% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">ST segment depression </td><td valign="top" styleCode="Rrule" align="center">3% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">First-degree AV block </td><td valign="top" styleCode="Rrule" align="center">3% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Second-degree AV block </td><td valign="top" styleCode="Rrule" align="center">3% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Paresthesia </td><td valign="top" styleCode="Rrule" align="center">2% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Hypotension </td><td valign="top" styleCode="Rrule" align="center">2% </td></tr><tr styleCode="Botrule"><td valign="top" styleCode="Lrule Rrule">Nervousness </td><td valign="top" styleCode="Rrule" align="center">2% </td></tr><tr><td valign="top" styleCode="Lrule Rrule">Arrhythmias </td><td valign="top" styleCode="Rrule" align="center">1% </td></tr></tbody></table>