Adenosine

Warnings and Precautions: Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction ( 5.1 ) 10/2013 Warnings and Precautions: Cerebrovascular Accidents ( 5.5 ) 8/2014 Warnings and Precautions: Seizures ( 5.6 ) 8/2014 Warnings and Precautions: Hypersensitivity ( 5.7 ) 8/2014

INDICATIONS AND USAGE: Intravenous adenosine injection, USP 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, USP administration. It is important to be sure the adenosine injection, USP solution actually reaches the systemic circulation (see DOSAGE AND ADMINISTRATION ). Adenosine injection, USP 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, USP administration.

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 intravenous 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 less than 50 kg: Initial dose: Give 0.05 mg/kg to 0.1 mg/kg as a rapid intravenous bolus given either centrally or peripherally. A saline flush should follow. Repeat administration: If conversion of paroxysmal supraventricular tachycardia 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 mg/kg 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 greater than or equal to 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.

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 less than 50 kg: Initial dose: Give 0.05 mg/kg to 0.1 mg/kg as a rapid intravenous bolus given either centrally or peripherally. A saline flush should follow. Repeat administration: If conversion of paroxysmal supraventricular tachycardia 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 mg/kg 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 greater than or equal to 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.

3 DOSAGE FORMS AND STRENGTHS Injection: 60 mg per 20 mL (3 mg per mL) and 90 mg per 30 mL (3 mg per mL) in single-dose vials containing a sterile, nonpyrogenic, clear, colorless solution of adenosine, USP. Injection: 60 mg per 20 mL (3 mg per mL) and 90 mg per 30 mL (3 mg per mL) in single-dose vials ( 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 (5.2) ] 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 injection [see Warnings and Precautions (5.7) ] 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 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: Fatal Cardiac Arrest, Ventricular Arrhythmias, and Myocardial Infarction [see Warnings and Precautions ( 5.1 )] Sinoatrial and Atrioventricular Nodal Block [see Warnings and Precautions ( 5.2 )] Bronchoconstriction [see Warnings and Precautions ( 5.3 )] Hypotension [see Warnings and Precautions ( 5.4 )] Cerebrovascular Accident [see Warnings and Precautions ( 5.5 )] Seizures [see Warnings and Precautions ( 5.6 )] Hypersensitivity [see Warnings and Precautions ( 5.7 )] Atrial fibrillation [see Warnings and Precautions ( 5.8 )] Hypertension [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (incidence ≥ 10%) are: flushing; chest discomfort; shortness of breath; headache; throat, neck or jaw discomfort; gastrointestinal discomfort; and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions, with an incidence of at least 1%, were reported with adenosine among 1,421 patients in clinical trials. 11% of the adverse reactions occurred several hours after adenosine administration. 8% of the adverse reactions began with adenosine infusion and persisted for up to 24 hours. The most common (incidence ≥ 10%) adverse reactions to adenosine are flushing, chest discomfort, shortness of breath, headache, throat, neck or jaw discomfort, gastrointestinal discomfort, and dizziness (Table 2). Table 2. Adverse Reactions in Clinical Trials (Frequency ≥ 1%) Adverse Reactions Adenosine N=1,421 Flushing 44% Chest discomfort 40% Dyspnea 28% Headache 18% Throat, neck or jaw discomfort 15% Gastrointestinal discomfort 13% Lightheadedness/dizziness 12% Upper extremity discomfort 4% ST segment depression 3% First-degree AV block 3% Second-degree AV block 3% Paresthesia 2% Hypotension 2% Nervousness 2% Arrhythmias 1% Adverse reactions to adenosine of any severity reported in less than 1% of patients include: Body as a Whole: back discomfort, lower extremity discomfort, weakness Cardiovascular System: myocardial infarction, ventricular arrhythmia, third-degree AV block, bradycardia, palpitation, sinus exit block, sinus pause, T-wave changes, hypertension (systolic blood pressure > 200 mm Hg) Respiratory System: cough Central Nervous System: drowsiness, emotional instability, tremors Genital/Urinary System: vaginal pressure, urgency Special Senses: blurred vision, dry mouth, ear discomfort, metallic taste, nasal congestion, scotomas, tongue discomfort 6.2 Post-Marketing Experience The following adverse reactions have been reported from marketing experience with adenosine. Because these reactions are reported voluntarily from a population of uncertain size, are associated with concomitant diseases and multiple drug therapies and surgical procedures, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac Disorders: cardiac arrest, atrial fibrillation, cardiac failure, myocardial infarction, tachycardia, ventricular arrhythmia Gastrointestinal Disorders: nausea and vomiting General Disorders and Administration Site Conditions: chest pain, injection site reaction, infusion site pain Immune System Disorders: hypersensitivity Nervous System Disorders: cerebrovascular accident including intracranial hemorrhage, seizure activity including tonic-clonic (grand mal) seizures, loss of consciousness Respiratory, Thoracic and Mediastinal Disorders: bronchospasm, respiratory arrest, throat tightness

6.1 Clinical Trials Experience Because clinic …

7 DRUG INTERACTIONS Methylxanthines interfere with the activity of adenosine injection ( 7.1 , 10 ) Nucleoside transport inhibitors such as dipyridamole can increase the activity of adenosine injection ( 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 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 (5.2) ] .

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 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.

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.

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: C 10 H 13 N 5 O 4 M.W. 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. Adenosine is not chemically related to other antiarrhythmic drugs. Adenosine injection, USP 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. The TopPac ® plastic syringe is molded from a specially formulated cyclo olefin copolymer. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts which have been toxicologically assessed and are within the safety margins. structure

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 mg 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) ] .

HOW SUPPLIED: Adenosine injection, USP is supplied as a sterile nonpyrogenic solution in normal saline, as follows: Product No. Unit of Sale Strength Each 605189 NDC 63323-651-89 Packaged individually in cartons of ten. 6 mg per 2 mL 2 mL fill, in a 5 mL(3 mg per mL) plastic prefilled syringe. NDC 63323-651-21 605190 NDC 63323-651-90 Packaged individually in cartons of ten. 12 mg per 4 mL 4 mL fill, in a 5 mL(3 mg per mL) plastic prefilled syringe. NDC 63323-651-23 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. Contains no preservatives. Discard unused portion. The container closure is not made with natural rubber latex. May require needle or blunt. To prevent needle-stick injuries, needles should not be recapped, purposely bent or broken by hand.