een 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 should be used with caution in the presence of these agents [see warnings and precautions ( 5.2 )] .

• 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 ( 5.6 ) • hypersensitivity . dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. have personnel and resuscitative equipment immediately available ( 5.7 ) • atrial fibrillation . reported in patients with or without a history of atrial fibrillation ( 5.8 ) • hypertension . clinically significant increases in systolic and diastolic pressure have been observed ( 5.9 ) 5.1 cardiac arrest, ventricular arrhythmias, and myocardial infarction fatal and nonfatal cardiac arrest, sustained ventricular tachycardia (requiring resuscitation), and myocardial infarction have occurred following adenosine infusion. avoid use in patients with symptoms or signs of acute myocardial ischemia, for example, unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to adenosine. appropriate resuscitative measures should be available [see overdosage ( 10 )] . 5.2 sinoatrial and atrioventricular nodal block adenosine exerts a direct depressant effect on the sa and av nodes and may cause first-, second- or third-degree av block, or sinus bradycardia. in clinical trials, approximately 6% of patients developed av block following adenosine administration (first-degree heart block developed in 3%, second-degree in 3%, and third-degree in 0.8% of patients) [see clinical trials experience ( 6.1 )] . use adenosine with caution in patients with pre-existing first-degree av block or bundle branch block. do not use in patients with high-grade av block or sinus node dysfunction (except in patients with a functioning artificial pacemaker). discontinue adenosine in any patient who develops persistent or symptomatic high-grade av block. 5.3 bronchoconstriction adenosine administration can cause dyspnea, bronchoconstriction, and respiratory compromise. adenosine should be used with caution in patients with obstructive lung disease not associated with bronchoconstriction (e.g., emphysema, bronchitis). do not use in patients with bronchoconstriction or bronchospasm (e.g., asthma). discontinue adenosine in any patient who develops severe respiratory difficulties. resuscitative measures should be available prior to adenosine administration [see clinical trials experience ( 6.1 ), overdosage ( 10 ), and clinical pharmacology ( 12.2 )]. 5.4 hypotension adenosine is a potent peripheral vasodilator and can induce significant hypotension. the risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. discontinue adenosine in any patient who develops persistent or symptomatic hypotension. 5.5 cerebrovascular accident hemorrhagic and ischemic cerebrovascular accidents have occurred. hemodynamic effects of adenosine including hypotension or hypertension can be associated with these adverse reactions [see warnings and precautions ( 5.4 ) and ( 5.9 )] . 5.6 seizures new-onset or recurrence of convulsive seizures has occurred following adenosine. some seizures are prolonged and require emergent anticonvulsive management. aminophylline may increase the risk of seizures associated with adenosine. methylxanthine use is not recommended in patients who experience seizures in association with adenosine administration [see overdosage ( 10 )]. 5.7 hypersensitivity, including anaphylaxis dyspnea, throat tightness, flushing, erythema, rash, and chest discomfort have occurred. symptomatic treatment may be required. have personnel and appropriate treatment available. resuscitative measures may be necessary if symptoms progress [see post-marketing experience ( 6.2 )]. 5.8 atrial fibrillation adenosine can cause atrial fibrillation in patients with or without a history of atrial fibrillation. atrial fibrillation typically began 1.5 to 3 minutes after initiation of adenosine, lasted for 15 seconds to 6 hours, and spontaneously converted to normal sinus rhythm [see post-marketing experience ( 6.2 )] . 5.9 hypertension adenosine can induce clinically significant increases in systolic and diastolic blood pressure. most increases resolved spontaneously within several minutes, but in some cases, hypertension lasted for several hours [see clinical trials experience ( 6.1 )] .

ion 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: 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 ) formula

verse reactions, contact mylan pharmaceuticals inc. at 1-877-446-3679 (1-877-4-info-rx) 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

een 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 should be used with caution in the presence of these agents [see warnings and precautions ( 5.2 )] .

e whether they respond differently. other reported experience has not revealed clinically relevant differences of the response of elderly in comparison to younger patients.

f thallium-201 is directly proportional to coronary blood flow. since adenosine significantly increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, adenosine causes relatively less thallium-201 uptake in vascular territories supplied by stenotic coronary arteries i.e., a greater difference is seen after adenosine between areas served by normal and areas served by stenotic vessels than is seen prior to adenosine. 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 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.

e 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.

rated that a dose of intravenous adenosine 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.

ings and precautions ( 5.6 ), drug interactions ( 7.1 ), and overdosage ( 10 )] . manufactured for: mylan institutional llc morgantown, wv 26505 u.s.a. manufactured by: mylan laboratories limited bangalore, india novaplus is a registered trademark of vizient, inc. may 2022