ADENOSINE

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- 5.1)] • Sinoatrial and Atrioventricular Nodal Block [ see Warnings and Precautions ( 5- 5.2)] • Bronchoconstriction [ see Warnings and Precautions ( 5- 5.3)] • Hypotension [ see Warnings and Precautions ( 5- 5.4)] • Cerebrovascular Accident [ see Warnings and Precautions ( 5- 5.5)] • Seizures [ see Warnings and Precautions ( 5- 5.6)] • Hypersensitivity [ see Warnings and Precautions ( 5- 5.7)] • Atrial fibrillation [ see Warnings and Precautions ( 5- 5.8)] • Hypertension [ see Warnings and Precautions ( 5- 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 infusion and persisted for up to 24 hours. The most common (incidence ≥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 ≥1%) Adverse reactions to adenosine injection of any severity reported in less than 1% of patients include: 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. ADVERSE REACTIONS 1 ADVERSE REACTIONS 2 ADVERSE REACTIONS 3

4 CONTRAINDICATIONS 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- 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- 5.2)] • Known or suspected bronchoconstrictive or bronchospastic lung disease (e.g., asthma) [ see Warnings and Precautions ( 5- 5.3)] • Known hypersensitivity to adenosine injection [ see Warnings and Precautions ( 5- 5.7)]

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, odorless crystalline powder. It is slightly soluble in water and practically insoluble in alcohol. Solubility increases by warming and lowering the pH of the solution. Each Adenosine Injection vial contains a sterile, non-pyrogenic solution of adenosine 3 mg/mL and sodium chloride 9 mg/mL in water for injection, with pH between 4.5 and 7.5. STRUCTURE

2 DOSAGE & ADMINISTRATION 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 The nomogram displayed in Table 1 was derived from the following general formula: 0.14 (mg/kg/min) x total body weight (kg) = Infusion rate (mL/min) Adenosine injection concentration (3 mg/mL) D AND A

1 INDICATIONS & USAGE Adenosine Injection is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately.

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- 7.1)].

7 DRUG INTERACTIONS 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 injection 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 Injection 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- 5.2)].

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 A1 and A2 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 A2 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 A1-receptor agonism, and produces peripheral vasodilation, presumably due to A2-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- 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 Km and Vmax 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.

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3 DOSAGE FORMS & STRENGTHS Adenosine Injection is supplied as 20 mL and 30 mL single-dose vials containing a sterile, nonpyrogenic, clear solution of adenosine 3mg/mL.

ADENOSINE ADENOSINE ADENOSINE ADENOSINE SODIUM CHLORIDE WATER

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.

ANDA203883

ADENOSINE

ADENOSINE

51662-1345

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 20 mL Vial Label 20 mL Single-Dose Vial NDC 0409-1932-01 Rx only Adenosine Injection, USP 60 mg/20 mL (3 mg/mL) Sterile For Intravenous Infusion Only Hospira VIAL LABEL

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ADENOSINE INJECTION, USP safely and effectively. See full prescribing information for ADENOSINE INJECTION, USP. ADENOSINE INJECTION, USP for intravenous use Initial U.S. Approval: 1995 RECENT MAJOR CHANGES Warnings and Precautions: Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction ( 5- 5.1) 10/2013 Warnings and Precautions: Cerebrovascular Accidents ( 5- 5.5) 8/2014 Warnings and Precautions: Seizures ( 5- 5.6) 8/2014 Warnings and Precautions: Hypersensitivity ( 5- 5.7) 8/2014 INDICATIONS AND USAGE Adenosine Injection, a pharmacologic stress agent, is indicated as an adjunct to thallium-201 myocardial perfusion scintigraphy in patients unable to exercise adequately ( 1 ) 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 ) DOSAGE FORMS AND STRENGTHS For Injection: 3 mg/mL in single-dose vials ( 3 ) 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 ) 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- 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- 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- 5.3) • Hypotension. Significant hypotension can occur. Discontinue adenosine injection if patient develops persistent or symptomatic hypotension ( 5- 5.4) • Cerebrovascular Accidents. Hemorrhagic and ischemic cerebrovascular accidents have occurred ( 5- 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- 5.6) • Hypersensitivity. Dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. Have personnel and resuscitative equipment immediately available ( 5- 5.7) • Atrial Fibrillation. Reported in patients with or without a history of atrial fibrillation ( 5- 5.8) • Hypertension. Clinically significant increases in systolic and diastolic pressure have been observed ( 5- 5.9) ADVERSE REACTIONS Most common adverse reactions (incidence ≥10%) are: flushing; chest discomfort; shortness of breath; headache; throat, neck or jaw discomfort; gastrointestinal discomfort; and dizziness ( 6- 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS • Methylxanthines interfere with the activity of adenosine injection ( 7- 7.1, 10 ) • Nucleoside transport inhibitors such as dipyridamole can increase the activity of adenosine injection ( 7- 7.1) See 17 for PATIENT COUNSELING INFORMATION. Revised: 7/2018

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 (≥ 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 infusion.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 injection is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from adenosine injection in nursing infants, the decision to interrupt nursing after administration of adenosine injection or not to administer adenosine injection, 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.

16 HOW SUPPLIED/STORAGE & HANDLING ADENOSINE INJECTION, USP is supplied in the following dosage forms. NDC 51662-1345-1 ADENOSINE INJECTION, USP 60mg/20mL (3mg/mL) 20mL VIAL HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms How Supplied Adenosine Injection, USP is supplied as 20 mL and 30 mL vials of sterile, nonpyrogenic, preservative-free, solution in normal saline: • 20 mL single-dose vial: NDC 0409-1932-01 60 mg/20 mL (3 mg/mL) in a 20 mL single-dose, flip-top glass vial, packed individually in a monocarton • 30 mL single-dose vial: NDC 0409-1932-02 90 mg/30 mL (3 mg/mL) in a 30 mL single-dose, flip-top glass vial, packed individually in a monocarton Storage and Handling • Store at controlled room temperature 20°C – 25°C (68°F – 77°F) • 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