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1 INDICATIONS AND USAGE Adenosine, a pharmacologic stress agent, is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately ( 1 ) Adenosine injection, USP is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

2 DOSAGE AND ADMINISTRATION Recommended dose is 0.14 mg/kg/min infused over six minutes as a continuous peripheral intravenous infusion (total dose of 0.84 mg/kg) ( 2 ) The recommended adenosine injection dose is 0.14 mg/kg/min infused over six minutes (total dose of 0.84 mg/kg) (Table 1). Administer adenosine injection only as a continuous peripheral intravenous infusion Inject Thallium-201 at the midpoint of the adenosine injection infusion (i.e., after the first three minutes of adenosine injection) Thallium-201 is physically compatible with adenosine injection and may be injected directly into the adenosine injection infusion set Inject Thallium-201 as close to the venous access as possible to prevent an inadvertent increase in the dose of adenosine injection (the contents of the intravenous tubing) being administered Visually inspect adenosine injection for particulate matter and discoloration prior to administration. Do not administer adenosine injection if it contains particulate matter or is discolored. There are no data on the safety or efficacy of alternative adenosine injection infusion protocols. The safety and efficacy of adenosine injection administered by the intracoronary route have not been established. Table 1 Dosage Chart for Adenosine Injection Patient Weight (kilograms) Infusion Rate (mL per minute over 6 minutes for total dose of 0.84 mg/kg) 45 2.1 50 2.3 55 2.6 60 2.8 65 3 70 3.3 75 3.5 80 3.8 85 4 90 4.2 The nomogram displayed in Table 1 was derived from the following general formula: formula

3 DOSAGE FORMS AND STRENGTHS For Injection: 3 mg/mL in single-dose vials ( 3 ) Adenosine injection, USP is supplied as 20 mL and 30 mL single-dose vials containing a sterile, nonpyrogenic, clear solution of adenosine 3 mg/mL.

4 CONTRAINDICATIONS Second- or third-degree AV block (except in patients with a functioning artificial pacemaker) ( 4 ) Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) ( 4 ) Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) ( 4 ) Known hypersensitivity to adenosine injection ( 4 ) Adenosine injection is contraindicated in patients with: Second- or third-degree AV block (except in patients with a functioning artificial pacemaker) [see Warnings and Precautions (5.2) ] Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker) [see Warnings and Precautions (5.2) ] Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) [see Warnings and Precautions (5.3) ] Known hypersensitivity to adenosine [see Warnings and Precautions (5.7) ]

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 injection 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 injection if patient develops severe respiratory difficulties ( 5.3 ) Hypotension. Significant hypotension can occur. Discontinue adenosine injection 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 a seizures in association with adenosine injection ( 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 injection 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 injection. Appropriate resuscitative measures should be available [see Overdosage (10) ]. 5.2 Sinoatrial and Atrioventricular Nodal Block Adenosine injection 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 injection 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 injection 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 injection in any patient who develops persistent or symptomatic high-grade AV block. 5.3 Bronchoconstriction Adenosine injection administration can cause dyspnea, bronchoconstriction, and respiratory compromise. Adenosine injection 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 injection in any patient who develops severe respiratory difficulties.

ection 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 injection in any patient who develops severe respiratory difficulties. Resuscitative measures should be available prior to adenosine injection administration [see Clinical Trials Experience (6.1) , Overdosage (10) , and Clinical Pharmacology (12.2) ]. 5.4 Hypotension Adenosine injection 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 injection in any patient who develops persistent or symptomatic hypotension. 5.5 Cerebrovascular Accident Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of adenosine injection 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 injection. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with adenosine injection. Methylxanthine use is not recommended in patients who experience seizures in association with adenosine injection administration [see Overdosage (10) ]. 5.7 Hypersensitivity 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 Clinical Trials Experience (6.1 )] . 5.8 Atrial Fibrillation Adenosine injection 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 injection, lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm [see Post-Marketing Experience (6.2) ]. 5.9 Hypertension Adenosine injection 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) ].

6 ADVERSE REACTIONS Most common adverse reactions (incidence greater than or equal to 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 Northstar Rx LLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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) ] 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 injection among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after adenosine injection administration. 8% of the adverse reactions began with adenosine injection infusion and persisted for up to 24 hours. The most common (incidence greater than or equal to 10%) adverse reactions to adenosine injection 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 Greater Than or Equal To 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 injection 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 greater than 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 injection. 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.

ith adenosine injection. 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 ID="ID332" width="446"><caption> Table 2 Adverse Reactions in Clinical Trials (Frequency Greater Than or Equal To 1%) </caption><colgroup><col width="228"/><col width="218"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="left" valign="top"><content styleCode="bold"> Adverse Reactions</content></td><td styleCode="Botrule Rrule Toprule" align="center" valign="top"><content styleCode="bold"> Adenosine </content> <content styleCode="bold"> N=</content><content styleCode="bold"> 1,421</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Flushing</td><td styleCode="Botrule Rrule" align="center" valign="top">44%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Chest discomfort</td><td styleCode="Botrule Rrule" align="center" valign="top">40%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Dyspnea</td><td styleCode="Botrule Rrule" align="center" valign="top">28%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Headache</td><td styleCode="Botrule Rrule" align="center" valign="top">18%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Throat, neck or jaw discomfort</td><td styleCode="Botrule Rrule" align="center" valign="top">15%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Gastrointestinal discomfort</td><td styleCode="Botrule Rrule" align="center" valign="top">13%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Lightheadedness/dizziness</td><td styleCode="Botrule Rrule" align="center" valign="top">12%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Upper extremity discomfort</td><td styleCode="Botrule Rrule" align="center" valign="top">4%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">ST segment depression</td><td styleCode="Botrule Rrule" align="center" valign="top">3%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">First-degree AV block</td><td styleCode="Botrule Rrule" align="center" valign="top">3%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Second-degree AV block</td><td styleCode="Botrule Rrule" align="center" valign="top">3%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Paresthesia</td><td styleCode="Botrule Rrule" align="center" valign="top">2%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Hypotension</td><td styleCode="Botrule Rrule" align="center" valign="top">2%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Nervousness</td><td styleCode="Botrule Rrule" align="center" valign="top">2%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Arrhythmias</td><td styleCode="Botrule Rrule" align="center" valign="top">1%</td></tr></tbody></table>

<tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Nervousness</td><td styleCode="Botrule Rrule" align="center" valign="top">2%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Arrhythmias</td><td styleCode="Botrule Rrule" align="center" valign="top">1%</td></tr></tbody></table> <table ID="ID333" width="590"><colgroup><col width="161"/><col width="429"/></colgroup><tbody><tr><td colspan="2" align="left" valign="top">Adverse reactions to adenosine injection of any severity reported in less than 1% of patients include:</td></tr><tr><td align="left" valign="top">Body as a Whole:</td><td align="left" valign="top">back discomfort, lower extremity discomfort, weakness</td></tr><tr><td align="left" valign="top">Cardiovascular System:</td><td align="left" valign="top">myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure greater than 200 mm Hg)</td></tr><tr><td align="left" valign="top">Respiratory System:</td><td align="left" valign="top">cough</td></tr><tr><td align="left" valign="top">Central nervous System:</td><td align="left" valign="top">drowsiness, emotional instability, tremors</td></tr><tr><td align="left" valign="top">Genital/Urinary System:</td><td align="left" valign="top">Vaginal pressure, urgency</td></tr><tr><td align="left" valign="top">Special Senses:</td><td align="left" valign="top">blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort</td></tr></tbody></table>

valign="top">Genital/Urinary System:</td><td align="left" valign="top">Vaginal pressure, urgency</td></tr><tr><td align="left" valign="top">Special Senses:</td><td align="left" valign="top">blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort</td></tr></tbody></table> <table ID="ID334" width="803"><colgroup><col width="371"/><col width="432"/></colgroup><tbody><tr><td align="left" valign="top">Cardiac Disorders:</td><td align="left" valign="top">cardiac arrest, atrial fibrillation, cardiac failure, myocardial infarction, tachycardia, ventricular arrhythmia</td></tr><tr><td align="left" valign="top">Gastrointestinal Disorders:</td><td align="left" valign="top">nausea and vomiting</td></tr><tr><td align="left" valign="top">General Disorders and Administration Site Conditions:</td><td align="left" valign="top">chest pain, injection site reaction, infusion site pain</td></tr><tr><td align="left" valign="top">Immune System Disorders:</td><td align="left" valign="top">hypersensitivity</td></tr><tr><td align="left" valign="top">Nervous System Disorders:</td><td align="left" valign="top">cerebrovascular accident including intracranial hemorrhage, seizure activity including tonic-clonic (grand mal) seizures, loss of consciousness</td></tr><tr><td align="left" valign="top">Respiratory, Thoracic and Mediastinal Disorders:</td><td align="left" valign="top">bronchospasm, respiratory arrest, throat tightness</td></tr></tbody></table>

7 DRUG INTERACTIONS Methylxanthines interfere with the activity of adenosine ( 7.1 , 10 ) Nucleoside transport inhibitors such as dipyridamole can increase the activity of adenosine ( 7.1 ) 7.1 Effects of Other Drugs on Adenosine Injection The vasoactive effects of adenosine are inhibited by adenosine receptor antagonists, (such as methylxanthines (e.g., caffeine, aminophylline, and theophylline). The safety and efficacy of adenosine injection in the presence of these agents has not been systematically evaluated [see Overdosage (10) ]. The vasoactive effects of adenosine are potentiated by nucleoside transport inhibitors such as dipyridamole. The safety and efficacy of adenosine in the presence of dipyridamole has not been systematically evaluated. Whenever possible, drugs that might inhibit or augment the effects of adenosine should be withheld for at least five half-lives prior to the use of adenosine injection. 7.2 Effects of Adenosine on Other Drugs Adenosine injection has been given with other cardioactive drugs (such as beta adrenergic blocking agents, cardiac glycosides, and calcium channel blockers) without apparent adverse interactions, but its effectiveness with these agents has not been systematically evaluated. Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine injection should be used with caution in the presence of these agents [see Warnings and Precautions (5.2) ].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. Because it is not known whether adenosine injection can cause fetal harm when administered to pregnant women, adenosine injection should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether adenosine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from adenosine in nursing infants, the decision to interrupt nursing after administration of adenosine injection or not to administer adenosine, should take into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of adenosine injection in patients less than 18 years of age have not been established. 8.5 Geriatric Use Clinical studies with adenosine injection did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently. Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients.

8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. Because it is not known whether adenosine injection can cause fetal harm when administered to pregnant women, adenosine injection should be used during pregnancy only if clearly needed.

8.3 Nursing Mothers It is not known whether adenosine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from adenosine in nursing infants, the decision to interrupt nursing after administration of adenosine injection or not to administer adenosine, should take into account the importance of the drug to the mother.

8.5 Geriatric Use Clinical studies with adenosine injection did not include sufficient numbers of subjects aged younger than 65 years to determine whether they respond differently. Other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients.

10 OVERDOSAGE The half-life of adenosine is less than 10 seconds and adverse reactions of adenosine injection usually resolve quickly when the infusion is discontinued, although delayed or persistent reactions have been observed. Methylxanthines, such as caffeine, aminophylline, and theophylline, are competitive adenosine receptor antagonists and theophylline has been used to terminate persistent adverse reactions. In clinical trials, theophylline (50 to 125 mg slow intravenous injection) was used to attenuate adenosine injection adverse reactions in approximately 2% of patients. Methylxanthine use is not recommended in patients who experience seizures in association with adenosine injection [see Drug Interactions (7.1) ].

11 DESCRIPTION Adenosine is an endogenous nucleoside and is chemically described as 6-amino-9-beta-D-ribofuranosyl-9-H-purine. Adenosine has the following structural formula: The molecular formula for adenosine is C 10 H 13 N 5 O 4 and its molecular weight is 267.24. Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH of the solution. Each adenosine injection, USP vial contains a sterile, non-pyrogenic solution of adenosine USP 3 mg/mL and sodium chloride USP 9 mg/mL in water for injection, USP with pH between 4.5 and 7.5. structural-formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Adenosine causes cardiac vasodilation which increases cardiac blood flow. Adenosine is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A 1 and A 2 adenosine receptors). Although the exact mechanism by which adenosine receptor activation relaxes vascular smooth muscle is not known, there is evidence to support both inhibition of the slow inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A 2 receptors in smooth muscle cells. Adenosine may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of adenosine is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, adenosine is rapidly phosphorylated by adenosine kinase to adenosine monophosphate, or deaminated by adenosine deaminase to inosine. These intracellular metabolites of adenosine are not vasoactive. Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since adenosine injection significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, adenosine injection causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after adenosine injection between areas served by normal and areas served by stenotic vessels than is seen prior to adenosine injection. 12.2 Pharmacodynamics Hemodynamic Effects Adenosine produces a direct negative chronotropic, dromotropic and inotropic effect on the heart, presumably due to A 1 -receptor agonism, and produces peripheral vasodilation, presumably due to A 2 -receptor agonism. The net effect of adenosine injection in humans is typically a mild to moderate reduction in systolic, diastolic and mean arterial blood pressure associated with a reflex increase in heart rate. Rarely, significant hypotension and tachycardia have been observed [see Warnings and Precautions (5.4) ]. 12.3 Pharmacokinetics Distribution Intravenously administered adenosine distributes from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Metabolism Intracellular adenosine is metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower K m and V max than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. Elimination While extracellular adenosine is primarily cleared from plasma by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. Specific Populations Renal Impairment As adenosine does not require renal function for its activation or inactivation, renal impairment would not be expected to alter its effectiveness or tolerability.

fe of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. Specific Populations Renal Impairment As adenosine does not require renal function for its activation or inactivation, renal impairment would not be expected to alter its effectiveness or tolerability. Hepatic Impairment As adenosine does not require hepatic function for its activation or inactivation, hepatic impairment would not be expected to alter its effectiveness or tolerability.

12.1 Mechanism of Action Adenosine causes cardiac vasodilation which increases cardiac blood flow. Adenosine is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A 1 and A 2 adenosine receptors). Although the exact mechanism by which adenosine receptor activation relaxes vascular smooth muscle is not known, there is evidence to support both inhibition of the slow inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A 2 receptors in smooth muscle cells. Adenosine may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of adenosine is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, adenosine is rapidly phosphorylated by adenosine kinase to adenosine monophosphate, or deaminated by adenosine deaminase to inosine. These intracellular metabolites of adenosine are not vasoactive. Myocardial uptake of thallium-201 is directly proportional to coronary blood flow. Since adenosine injection significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, adenosine injection causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after adenosine injection between areas served by normal and areas served by stenotic vessels than is seen prior to adenosine injection.

12.2 Pharmacodynamics Hemodynamic Effects Adenosine produces a direct negative chronotropic, dromotropic and inotropic effect on the heart, presumably due to A 1 -receptor agonism, and produces peripheral vasodilation, presumably due to A 2 -receptor agonism. The net effect of adenosine injection in humans is typically a mild to moderate reduction in systolic, diastolic and mean arterial blood pressure associated with a reflex increase in heart rate. Rarely, significant hypotension and tachycardia have been observed [see Warnings and Precautions (5.4) ].

12.3 Pharmacokinetics Distribution Intravenously administered adenosine distributes from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Metabolism Intracellular adenosine is metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower K m and V max than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. Elimination While extracellular adenosine is primarily cleared from plasma by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. Specific Populations Renal Impairment As adenosine does not require renal function for its activation or inactivation, renal impairment would not be expected to alter its effectiveness or tolerability. Hepatic Impairment As adenosine does not require hepatic function for its activation or inactivation, hepatic impairment would not be expected to alter its effectiveness or tolerability.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate adenosine's carcinogenic potential or potential effects on fertility. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate adenosine's carcinogenic potential or potential effects on fertility. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations.

14 CLINICAL STUDIES In two crossover comparative studies involving 319 subjects who could exercise (including 106 healthy volunteers and 213 patients with known or suspected coronary disease), adenosine injection and exercise thallium images were compared by blinded observers. The images were concordant for the presence of perfusion defects in 85.5% of cases by global analysis (patient by patient) and up to 93% of cases based on vascular territories. In the two studies, 193 patients also had recent coronary arteriography for comparison (healthy volunteers were not catheterized). The sensitivity for detecting angiographically significant disease (greater than or equal to 50% reduction in the luminal diameter of at least one major vessel) was 64% for adenosine injection and 64% for exercise testing. The specificity was 54% for adenosine injection and 65% for exercise testing. The 95% confidence limits for adenosine injection sensitivity were 56% to 78% and for specificity were 37% to 71%. Intracoronary Doppler flow catheter studies have demonstrated that a dose of intravenous adenosine injection of 0.14 mg/kg/min produces maximum coronary hyperemia (relative to intracoronary papaverine) in approximately 95% of cases within two to three minutes of the onset of the infusion. Coronary blood flow velocity returns to basal levels within one to two minutes of discontinuing the adenosine injection infusion.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Adenosine injection, USP is supplied as 20 mL and 30 mL vials of sterile, nonpyrogenic, preservative-free, solution in normal saline: 60 mg/20 mL (3 mg/mL) in a 20 mL single-dose, glass vial, packaged individually in a carton (NDC 16714-556-01). 90 mg/30 mL (3 mg/mL) in a 30 mL single-dose, glass vial, packaged individually in a carton (NDC 16714-997-01). 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature] Do not refrigerate as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use Discard unused portion

17 PATIENT COUNSELING INFORMATION Advise patients that they may be at increased risk of fatal and nonfatal heart attacks, abnormal heart rhythms, cardiac arrest, heart block, significant increase or decrease in blood pressure, bronchoconstriction, hypersensitivity reactions, seizures, or cerebrovascular accidents with the use of adenosine injection [see Warnings and Precautions (5.1 to 5.9) ]. Advise patients with COPD or asthma to discuss their respiratory history with their clinician before scheduling a myocardial perfusion imaging study with adenosine injection [see Warnings and Precautions (5.3) ]. Methylxanthines have the potential to impact the effects of adenosine injection. Instruct patients to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine- containing drug products, aminophylline, and theophylline prior to the myocardial perfusion imaging study. Question patients about a history of seizures [see Warnings and Precautions (5.6) , Drug Interactions (7.1) , and Overdosage (10) ]. Manufactured by: Emcure Pharmaceuticals Ltd., Sanand, Ahmedabad-382110, India. Manufactured for: Northstar Rx LLC Memphis, TN 38141. Revised: 06/2022

Description Adenosine is an endogenous nucleoside occurring in all cells of the body. It is chemically 6-amino-9-β-D-ribofuranosyl-9-H-purine and has the following structural formula: Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH. Adenosine is not chemically related to other antiarrhythmic drugs. Adenosine Injection is a sterile, nonpyrogenic solution for rapid bolus intravenous injection. Each mL contains 3 mg adenosine and 9 mg sodium chloride in Water for Injection. The pH of the solution is between 4.5 and 7.5. Structural Formula

Clinical Pharmacology Mechanism of Action Adenosine Injection slows conduction time through the A-V node, can interrupt the reentry pathways through the A-V node, and can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White Syndrome. Adenosine Injection is antagonized competitively by methylxanthines such as caffeine and theophylline, and potentiated by blockers of nucleoside transport such as dipyridamole. Adenosine Injection is not blocked by atropine. Hemodynamics The intravenous bolus dose of 6 or 12 mg adenosine injection usually has no systemic hemodynamic effects. When larger doses are given by infusion, adenosine decreases blood pressure by decreasing peripheral resistance. Pharmacokinetics Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower K m and V max than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. As adenosine injection requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability. Clinical Trial Results In controlled studies in the United States, bolus doses of 3, 6, 9, and 12 mg were studied. A cumulative 60% of patients with paroxysmal supraventricular tachycardia had converted to normal sinus rhythm within one minute after an intravenous bolus dose of 6 mg adenosine injection (some converted on 3 mg and failures were given 6 mg), and a cumulative 92% converted after a bolus dose of 12 mg. Seven to sixteen percent of patients converted after 1 to 4 placebo bolus injections. Similar responses were seen in a variety of patient subsets, including those using or not using digoxin, those with Wolff-Parkinson-White Syndrome, males, females, blacks, Caucasians, and Hispanics. Adenosine is not effective in converting rhythms other than PSVT, such as atrial flutter, atrial fibrillation, or ventricular tachycardia, to normal sinus rhythm.

Mechanism of Action Adenosine Injection slows conduction time through the A-V node, can interrupt the reentry pathways through the A-V node, and can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White Syndrome. Adenosine Injection is antagonized competitively by methylxanthines such as caffeine and theophylline, and potentiated by blockers of nucleoside transport such as dipyridamole. Adenosine Injection is not blocked by atropine.

Pharmacokinetics Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower K m and V max than adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. As adenosine injection requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability.

Indications and Usage Intravenous adenosine injection is indicated for the following. Conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White Syndrome). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver), should be attempted prior to adenosine injection administration. It is important to be sure the adenosine injection solution actually reaches the systemic circulation (see DOSAGE AND ADMINISTRATION ). Adenosine Injection does not convert atrial flutter, atrial fibrillation, or ventricular tachycardia to normal sinus rhythm. In the presence of atrial flutter or atrial fibrillation, a transient modest slowing of ventricular response may occur immediately following adenosine injection administration.

Contraindications Intravenous adenosine injection is contraindicated in: Second- or third-degree A-V block (except in patients with a functioning artificial pacemaker). Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker). Known hypersensitivity to adenosine.

Warnings Heart Block Adenosine Injection exerts its effect by decreasing conduction through the A-V node and may produce a short lasting first-, second- or third-degree heart block. Appropriate therapy should be instituted as needed. Patients who develop high-level block on one dose of adenosine injection should not be given additional doses. Because of the very short half-life of adenosine, these effects are generally self-limiting. Appropriate resuscitative measures should be available. Transient or prolonged episodes of asystole have been reported with fatal outcomes in some cases. Rarely, ventricular fibrillation has been reported following adenosine injection administration, including both resuscitated and fatal events. In most instances, these cases were associated with the concomitant use of digoxin and, less frequently with digoxin and verapamil. Although no causal relationship or drug-drug interaction has been established, adenosine injection should be used with caution in patients receiving digoxin or digoxin and verapamil in combination. Arrhythmias at Time of Conversion At the time of conversion to normal sinus rhythm, a variety of new rhythms may appear on the electrocardiogram. They generally last only a few seconds without intervention, and may take the form of premature ventricular contractions, atrial premature contractions, atrial fibrillation, sinus bradycardia, sinus tachycardia, skipped beats, and varying degrees of A-V nodal block. Such findings were seen in 55% of patients. Bronchoconstriction Adenosine Injection is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (Ve) and reduce arterial PCO 2 causing respiratory alkalosis. Adenosine administered by inhalation has been reported to cause bronchoconstriction in asthmatic patients, presumably due to mast cell degranulation and histamine release. These effects have not been observed in normal subjects. Adenosine Injection has been administered to a limited number of patients with asthma and mild to moderate exacerbation of their symptoms has been reported. Respiratory compromise has occurred during adenosine infusion in patients with obstructive pulmonary disease. Adenosine Injection should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenosine Injection should be discontinued in any patient who develops severe respiratory difficulties.

Precautions Drug Interactions Intravenous adenosine injection has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with adenosine injection (see WARNINGS ). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine injection should be used with caution in the presence of these agents. The use of adenosine injection in patients receiving digitalis may be rarely associated with ventricular fibrillation (see WARNINGS ). The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate the carcinogenic potential of adenosine injection. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. Fertility studies in animals have not been conducted with adenosine. Pregnancy Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether adenosine injection can cause fetal harm when administered to pregnant women, adenosine injection should be used during pregnancy only if clearly needed. Pediatric Use No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of adenosine injection for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents (see DOSAGE AND ADMINISTRATION ). Geriatric Use Clinical studies of adenosine injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, adenosine injection in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block.

Drug Interactions Intravenous adenosine injection has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with adenosine injection (see WARNINGS ). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine injection should be used with caution in the presence of these agents. The use of adenosine injection in patients receiving digitalis may be rarely associated with ventricular fibrillation (see WARNINGS ). The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine.

Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate the carcinogenic potential of adenosine injection. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. Fertility studies in animals have not been conducted with adenosine.

Pregnancy Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether adenosine injection can cause fetal harm when administered to pregnant women, adenosine injection should be used during pregnancy only if clearly needed.

Teratogenic Effects: Pregnancy Category C: Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether adenosine injection can cause fetal harm when administered to pregnant women, adenosine injection should be used during pregnancy only if clearly needed.

Pediatric Use No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of adenosine injection for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents (see DOSAGE AND ADMINISTRATION ).

Geriatric Use Clinical studies of adenosine injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, adenosine injection in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block.

Adverse Reactions The following reactions were reported with intravenous adenosine injection used in controlled U.S. clinical trials. The placebo group had a less than 1% rate of all of these reactions. Cardiovascular Facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (less than 1%). Respiratory Shortness of breath/dyspnea (12%), chest pressure (7%), hyperventilation, head pressure (less than 1%). Central Nervous System Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in arms, neck and back pain (less than 1%). Gastrointestinal Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%). Post Marketing Experience ( see WARNINGS ) The following adverse events have been reported from marketing experience with adenosine injection. Because these events 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. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, (3) strength of causal connection to the drug, or a combination of these factors. Cardiovascular Prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood pressure, bradycardia, atrial fibrillation, and Torsade de Pointes Respiratory Bronchospasm Central Nervous System Seizure activity, including tonic clonic (grand mal) seizures, and loss of consciousness. To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage The half-life of adenosine injection is less than 10 seconds. Thus, adverse effects are generally rapidly self-limiting. Treatment of any prolonged adverse effects should be individualized and be directed toward the specific effect. Methylxanthines, such as caffeine and theophylline, are competitive antagonists of adenosine.

Dosage and Administration For rapid bolus intravenous use only. Adenosine Injection, USP should be given as a rapid bolus by the peripheral intravenous route. To be certain the solution reaches the systemic circulation, it should be administered either directly into a vein or, if given into an IV line, it should be given as close to the patient as possible and followed by a rapid saline flush. Adult Patients The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of adenosine injection has not been systematically studied. The recommended intravenous doses for adults are as follows: Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1 to 2 second period). Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12 mg dose may be repeated a second time if required. Pediatric Patients The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis. Pediatric Patients with a Body Weight < 50 kg: Initial dose: Give 0.05 to 0.1 mg/kg as a rapid IV bolus given either centrally or peripherally. A saline flush should follow. Repeat administration: If conversion of PSVT does not occur within 1-2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used. Pediatric Patients with a Body Weight ≥ 50 kg: Administer the adult dose. Doses greater than 12 mg are not recommended for adult and pediatric patients. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

How Supplied Adenosine Injection, USP is supplied as a sterile non-pyrogenic solution in normal saline. NDC Adenosine Injection, USP (3 mg per mL) Package Factor 84549-318-02 6 mg per 2 mL Single-Dose Vial 1 vial Storage Conditions Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] DO NOT REFRIGERATE as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.

<table width="100%" styleCode="Noautorules"><colgroup><col align="left" width="20.700%"/><col align="left" width="53.700%"/><col align="left" width="25.600%"/></colgroup><tbody><tr><td align="justify" valign="top"><content styleCode="bold">NDC</content></td><td align="justify" valign="top"><content styleCode="bold">Adenosine Injection, USP (3 mg per mL)</content></td><td align="justify" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="justify" valign="top">84549-318-02</td><td align="justify" valign="top">6 mg per 2 mL Single-Dose Vial</td><td align="justify" valign="top">1 vial</td></tr><tr><td align="justify" valign="top"/><td align="justify" valign="top"/><td align="justify" valign="top"/></tr></tbody></table>

Storage Conditions Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] DO NOT REFRIGERATE as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear at the time of use. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.

REFERENCE Paul T, Pfammatter. J-P. Adenosine: an effective and safe antiarrhythmic drug in pediatrics. Pediatric Cardiology 1997; 18:118-126 SAGENT ® Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60195 (USA) Made in India ©2023 Sagent Pharmaceuticals, Inc. January 2023 SAGENT Pharmaceuticals ®

DESCRIPTION Adenosine is an endogenous nucleoside occurring in all cells of the body. It is chemically 6-amino-9-ß-D-ribofuranosyl-9-H-purine and has the following structural formula: Adenosine is a white crystalline powder. It is soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH. Adenosine is not chemically related to other antiarrhythmic drugs. Adenosine Injection is a sterile, nonpyrogenic solution for rapid bolus intravenous injection. Each mL contains 3 mg adenosine and 9 mg sodium chloride in water for injection. The pH of the solution is between 4.5 and 7.5. STRUCTURE

CLINICAL PHARMACOLOGY Mechanism of Action Adenosine slows conduction time through the A-V node, can interrupt the re-entry pathways through the A-V node, and can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White Syndrome. Adenosine is antagonized competitively by methylxanthines such as caffeine and theophylline, and potentiated by blockers of nucleoside transport such as dipyridamole. Adenosine is not blocked by atropine. Hemodynamics The intravenous bolus dose of 6 or 12 mg adenosine injection usually has no systemic hemodynamic effects. When larger doses are given by infusion, adenosine decreases blood pressure by decreasing peripheral resistance. Pharmacokinetics Intravenously administered adenosine is rapidly cleared from the circulation via cellular uptake, primarily by erythrocytes and vascular endothelial cells. This process involves a specific transmembrane nucleoside carrier system that is reversible, nonconcentrative, and bidirectionally symmetrical. Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Since adenosine kinase has a lower K m and V maxthan adenosine deaminase, deamination plays a significant role only when cytosolic adenosine saturates the phosphorylation pathway. Inosine formed by deamination of adenosine can leave the cell intact or can be degraded to hypoxanthine, xanthine, and ultimately uric acid. Adenosine monophosphate formed by phosphorylation of adenosine is incorporated into the high-energy phosphate pool. While extracellular adenosine is primarily cleared by cellular uptake with a half-life of less than 10 seconds in whole blood, excessive amounts may be deaminated by an ecto-form of adenosine deaminase. As adenosine requires no hepatic or renal function for its activation or inactivation, hepatic and renal failure would not be expected to alter its effectiveness or tolerability. Clinical Trial Results In controlled studies in the United States, bolus doses of 3, 6, 9, and 12 mg were studied. A cumulative 60% of patients with paroxysmal supraventricular tachycardia had converted to normal sinus rhythm within one minute after an intravenous bolus dose of 6 mg adenosine injection (some converted on 3 mg and failures were given 6 mg), and a cumulative 92% converted after a bolus dose of 12 mg. Seven to sixteen percent of patients converted after 1 to 4 placebo bolus injections. Similar responses were seen in a variety of patient subsets, including those using or not using digoxin, those with Wolff-Parkinson-White Syndrome, males, females, blacks, Caucasians, and Hispanics. Adenosine is not effective in converting rhythms other than PSVT, such as atrial flutter, atrial fibrillation, or ventricular tachycardia, to normal sinus rhythm.

INDICATIONS & USAGE Intravenous adenosine injection is indicated for the following: Conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including that associated with accessory bypass tracts (Wolff-Parkinson-White Syndrome). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver), should be attempted prior to adenosine injection administration. It is important to be sure the adenosine injection solution actually reaches the systemic circulation (see DOSAGE & ADMINISTRATION . Adenosine injection does not convert atrial flutter, atrial fibrillation, or ventricular tachycardia to normal sinus rhythm. In the presence of atrial flutter or atrial fibrillation, a transient modest slowing of ventricular response may occur immediately following adenosine injection administration.

CONTRAINDICATIONS Intravenous adenosine injection is contraindicated in: Second- or third-degree A-V block (except in patients with a functioning artificial pacemaker). Sinus node disease, such as sick sinus syndrome or symptomatic bradycardia (except in patients with a functioning artificial pacemaker). Known hypersensitivity to adenosine.

WARNINGS Heart Block Adenosine injection exerts its effect by decreasing conduction through the A-V node and may produce a short lasting first-, second- or third-degree heart block. Appropriate therapy should be instituted as needed. Patients who develop high-level block on one dose of adenosine should not be given additional doses. Because of the very short half-life of adenosine, these effects are generally self-limiting. Appropriate resuscitative measures should be available. Transient or prolonged episodes of asystole have been reported with fatal outcomes in some cases. Rarely, ventricular fibrillation has been reported following adenosine administration, including both resuscitated and fatal events. In most instances, these cases were associated with the concomitant use of digoxin and, less frequently with digoxin and verapamil. Although no causal relationship or drug-drug interaction has been established, adenosine should be used with caution in patients receiving digoxin or digoxin and verapamil in combination. Arrhythmias at Time of Conversion At the time of conversion to normal sinus rhythm, a variety of new rhythms may appear on the electrocardiogram. They generally last only a few seconds without intervention, and may take the form of premature ventricular contractions, atrial premature contractions, atrial fibrillation, sinus bradycardia, sinus tachycardia, skipped beats, and varying degrees of A-V nodal block. Such findings were seen in 55% of patients. Bronchoconstriction Adenosine injection is a respiratory stimulant (probably through activation of carotid body chemoreceptors) and intravenous administration in man has been shown to increase minute ventilation (Ve) and reduce arterial PCO 2 causing respiratory alkalosis. Adenosine administered by inhalation has been reported to cause bronchoconstriction in asthmatic patients, presumably due to mast cell degranulation and histamine release. These effects have not been observed in normal subjects. Adenosine injection has been administered to a limited number of patients with asthma and mild to moderate exacerbation of their symptoms has been reported. Respiratory compromise has occurred during adenosine infusion in patients with obstructive pulmonary disease. Adenosine injection should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis, etc.) and should be avoided in patients with bronchoconstriction or bronchospasm (e.g., asthma). Adenosine injection should be discontinued in any patient who develops severe respiratory difficulties.

PRECAUTIONS Drug Interactions Intravenous adenosine injection has been effectively administered in the presence of other cardioactive drugs, such as quinidine, beta-adrenergic blocking agents, calcium channel blocking agents, and angiotensin converting enzyme inhibitors, without any change in the adverse reaction profile. Digoxin and verapamil use may be rarely associated with ventricular fibrillation when combined with adenosine injection (see WARNINGS ). Because of the potential for additive or synergistic depressant effects on the SA and AV nodes, however, adenosine injection should be used with caution in the presence of these agents. The use of adenosine injection in patients receiving digitalis may be rarely associated with ventricular fibrillation (see WARNINGS ). The effects of adenosine are antagonized by methylxanthines such as caffeine and theophylline. In the presence of these methylxanthines, larger doses of adenosine may be required or adenosine may not be effective. Adenosine effects are potentiated by dipyridamole. Thus, smaller doses of adenosine may be effective in the presence of dipyridamole. Carbamazepine has been reported to increase the degree of heart block produced by other agents. As the primary effect of adenosine is to decrease conduction through the A-V node, higher degrees of heart block may be produced in the presence of carbamazepine. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals have not been performed to evaluate the carcinogenic potential of adenosine injection. Adenosine was negative for genotoxic potential in the Salmonella (Ames Test) and Mammalian Microsome Assay. Adenosine, however, like other nucleosides at millimolar concentrations present for several doubling times of cells in culture, is known to produce a variety of chromosomal alterations. Fertility studies in animals have not been conducted with adenosine. Pregnancy Category C Animal reproduction studies have not been conducted with adenosine; nor have studies been performed in pregnant women. As adenosine is a naturally occurring material, widely dispersed throughout the body, no fetal effects would be anticipated. However, since it is not known whether adenosine injection can cause fetal harm when administered to pregnant women, adenosine injection should be used during pregnancy only if clearly needed. Pediatric Use No controlled studies have been conducted in pediatric patients to establish the safety and efficacy of adenosine injection for the conversion of paroxysmal supraventricular tachycardia (PSVT). However, intravenous adenosine has been used for the treatment of PSVT in neonates, infants, children and adolescents (see DOSAGE AND ADMINISTRATION ). Geriatric Use Clinical studies of adenosine injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, adenosine injection in geriatric patients should be used with caution since this population may have a diminished cardiac function, nodal dysfunction, concomitant diseases or drug therapy that may alter hemodynamic function and produce severe bradycardia or AV block.

ADVERSE REACTIONS The following reactions were reported with intravenous adenosine injection used in controlled U.S. clinical trials. The placebo group had a less than 1% rate of all of these reactions. Cardiovascular Facial flushing (18%), headache (2%), sweating, palpitations, chest pain, hypotension (less than 1%). Respiratory Shortness of breath/dyspnea (12%), chest pressure (7%), hyperventilation, head pressure (less than 1%). Central Nervous System Lightheadedness (2%), dizziness, tingling in arms, numbness (1%), apprehension, blurred vision, burning sensation, heaviness in arms, neck and back pain (less than 1%). Gastrointestinal Nausea (3%), metallic taste, tightness in throat, pressure in groin (less than 1%). Post Marketing Experience (see WARNINGS ) The following adverse events have been reported from marketing experience with adenosine injection. Because these events 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. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, (3) strength of causal connection to the drug, or a combination of these factors. Cardiovascular Prolonged asystole, ventricular tachycardia, ventricular fibrillation, transient increase in blood pressure, bradycardia, atrial fibrillation, and Torsades de Pointes. Respiratory Bronchospasm. Central Nervous System Seizure activity, including tonic clonic (grand mal) seizures, and loss of consciousness.

OVERDOSAGE The half-life of adenosine injection is less than 10 seconds. Thus, adverse effects are generally rapidly self-limiting. Treatment of any prolonged adverse effects should be individualized and be directed toward the specific effect. Methylxanthines, such as caffeine and theophylline, are competitive antagonists of adenosine.

DOSAGE & ADMINISTRATION For rapid bolus intravenous use only. Adenosine Injection, USP should be given as a rapid bolus by the peripheral intravenous route. To be certain the solution reaches the systemic circulation, it should be administered either directly into a vein or, if given into an IV line, it should be given as close to the patient as possible and followed by a rapid saline flush. Adult Patients The dose recommendation is based on clinical studies with peripheral venous bolus dosing. Central venous (CVP or other) administration of Adenosine Injection, USP has not been systematically studied. The recommended intravenous doses for adults are as follows: Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1 to 2 second period). Repeat administration: If the first dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes, 12 mg should be given as a rapid intravenous bolus. This 12 mg dose may be repeated a second time if required. Pediatric Patients The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis. Pediatric Patients with a Body Weight < 50 kg: Initial dose: give 0.05 to 0.1 mg/kg as a rapid IV bolus either centrally or peripherally. A saline flush should follow. Repeat administration: If conversion of PSVT does not occur within 1 to 2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg. Follow each bolus with a saline flush. This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used. Pediatric Patients with a Body Weight > 50 kg: Administer the adult dose. Doses greater than 12 mg are not recommended for adult and pediatric patients. NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

HOW SUPPLIED ADENOSINE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1450-1 ADENOSINE INJECTION, USP 12mg/4mL (3mg/mL) 4mL VIAL HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms Adenosine Injection, USP is supplied as a sterile, non-pyrogenic solution in normal saline. Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. DO NOT REFRIGERATE as crystallization may occur. If crystallization has occurred, dissolve crystals by warming to room temperature. The solution must be clear and particle free at the time of use. CONTAINS NO PRESERVATIVES. DISCARD UNUSED PORTION. This container closure is not made with natural rubber latex. HOW SUPPLIED