Regadenoson

INDICATIONS AND USAGE LEXISCAN ® (regadenoson) injection is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress. LEXISCAN ® is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress ( 1 ).

DOSAGE AND ADMINISTRATION The recommended dose of regadenoson injection is 5 mL (0.4 mg regadenoson) administered as an intravenous injection within 10 seconds. • Patients should be instructed to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine-containing drug products, aminophylline and theophylline for at least 12 hours before a scheduled radionuclide MPI [see Drug Interactions (7.1) and Clinical Pharmacology (12.2) ] . • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer regadenoson injection if it contains particulate matter or is discolored. • Administer regadenoson injection as an intravenous injection within 10 seconds into a peripheral vein using a 22 gauge or larger catheter or needle. • Administer a 5 mL saline flush immediately after the injection of regadenoson injection. • Administer the radionuclide myocardial perfusion imaging agent 10–20 seconds after the saline flush. The radionuclide may be injected directly into the same catheter as regadenoson injection. The recommended dose of regadenoson injection is 5 mL (0.4 mg regadenoson) administered as an intravenous injection within 10 seconds; followed immediately by saline flush and radiopharmaceutical ( 2 ).

WARNINGS AND PRECAUTIONS Myocardial Ischemia. Fatal cardiac events have occurred. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example unstable angina or cardiovascular instability, who may be at greater risk. Cardiac resuscitation equipment and trained staff should be available before administration (5.1) . Sinoatrial (SA) and Atrioventricular (AV) Nodal Block. Adenosine receptor agonists, including regadenoson injection, can depress the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia (5.2) . Atrial Fibrillation/Atrial Flutter. New-onset or recurrent atrial fibrillation with rapid ventricular response and atrial flutter have been reported (5.3) . Hypersensitivity, including anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria, and rashes have occurred. Have personnel and resuscitative equipment immediately available (5.4). Hypotension. Adenosine receptor agonists, including regadenoson injection, induce vasodilation and hypotension. The risk of serious hypotension may be higher in patients with autonomic dysfunction, stenotic valvular heart disease, pericarditis or pericardial effusions, stenotic carotid artery disease with cerebrovascular insufficiency, or hypovolemia (5.5) . Hypertension. Adenosine receptor agonists, including regadenoson injection, may induce clinically significant increases in blood pressure particularly in patients with a history of hypertension and when the MPI includes low level exercise (5.6) . Bronchoconstriction. Adenosine receptor agonists, including regadenoson injection, may induce dyspnea, bronchoconstriction and respiratory compromise in patients with chronic obstructive pulmonary disease (COPD) or asthma. Resuscitative measures should be available ( 5.7 ). Seizure. regadenoson injection may lower the seizure threshold. New onset or recurrence of convulsive seizures has occurred. Some seizures are prolonged and require urgent anticonvulsive management. Methylxanthine use is not recommended in patients who experience a seizure in association with regadenoson injection (5.8). Cerebrovascular Accident (Stroke). Hemorrhagic and ischemic cerebrovascular accidents have occurred (5.9). 5.1 Myocardial Ischemia Fatal and nonfatal myocardial infarction (MI), ventricular arrhythmias, and cardiac arrest have occurred following regadenoson. 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 regadenoson. Cardiac resuscitation equipment and trained staff should be available before administering regadenoson. Adhere to the recommended duration of injection [see Dosage and Administration ( 2 )]. As noted in an animal study, longer injection times may increase the duration and magnitude of increase in coronary blood flow [see Clinical Pharmacology ( 12.2) ]. If serious reactions to regadenoson injection occur, consider the use of aminophylline, an adenosine antagonist, to shorten the duration of increased coronary blood flow induced by regadenoson [see Overdosage ( 10) ]. 5.2 Sinoatrial and Atrioventricular Nodal Block Adenosine receptor agonists, including regadenoson, can depress the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia requiring intervention. In clinical trials first-degree AV block (PR prolongation > 220 msec) developed in 3% of patients within 2 hours of regadenoson administration; transient second-degree AV block with one dropped beat was observed in one patient receiving regadenoson. In post-marketing experience, third-degree heart block and asystole within minutes of regadenoson administration have occurred [see Adverse Reactions ( 6.2) ]. 5.3 Atrial Fibrillation/Atrial Flutter New-onset or recurrent atrial fibrillation with rapid ventricular response and atrial flutter have been reported following regadenoson [see Adverse Reactions ( 6.2) ]. 5.4 Hypersensitivity, Including Anaphylaxis Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria and rashes have occurred. In clinical trials, hypersensitivity reactions were reported in fewer than 1 percent of patients [see Adverse Reactions ( 6.1) ]. Have personnel and resuscitative equipment immediately available. 5.5 Hypotension Adenosine receptor agonists, including regadenoson, induce arterial vasodilation and hypotension. In clinical trials, decreased systolic blood pressure (> 35 mm Hg) was observed in 7% of patients and decreased diastolic blood pressure (> 25 mm Hg) was observed in 4% of patients within 45 minutes of regadenoson administration. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. In post-marketing experience, syncope, transient ischemic attacks and seizures have been observed [see Adverse Reactions ( 6.2) ]. 5.6 Hypertension Administration of adenosine receptor agonists, including regadenoson, may result in clinically significant increases in blood pressure in some patients. Among patients who experienced an increase in blood pressure in clinical trials, the increase was observed within minutes of regadenoson administration. Most increases resolved within 10 to 15 minutes, but in some cases, increases were observed at 45 minutes following administration [see Clinical Pharmacology ( 12.2) ]. In post-marketing experience, cases of potentially clinically significant hypertension have been reported, particularly with underlying hypertension and when low-level exercise was included in the MPI [see Adverse Reactions ( 6.2) ]. 5.7 Bronchoconstriction Adenosine receptor agonists, including regadenoson, may cause dyspnea, bronchoconstriction, and respiratory compromise. Appropriate bronchodilator therapy and resuscitative measures should be available prior to and following regadenoson administration [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2) , Overdosage ( 10) and Patient Counseling Information ( 17) ]. 5.8 Seizure Regadenoson may lower the seizure threshold; obtain a seizure history. New-onset or recurrence of convulsive seizures has occurred following regadenoson. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with regadenoson. Methylxanthine use is not recommended in patients who experience a seizure in association with regadenoson administration. 5.9 Cerebrovascular Accident (Stroke) Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of regadenoson including hypotension or hypertension may be associated with these adverse reactions [see Warnings and Precautions ( 5.5) and ( 5.6 ) ]. 5.1 Myocardial Ischemia Fatal and nonfatal myocardial infarction (MI), ventricular arrhythmias, and cardiac arrest have occurred following regadenoson. 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 regadenoson. Cardiac resuscitation equipment and trained staff should be available before administering regadenoson. Adhere to the recommended duration of injection [see Dosage and Administration ( 2 )]. As noted in an animal study, longer injection times may increase the duration and magnitude of increase in coronary blood flow [see Clinical Pharmacology ( 12.2) ]. If serious reactions to regadenoson injection occur, consider the use of aminophylline, an adenosine antagonist, to shorten the durat

CONTRAINDICATIONS Do not administer Regadenoson injection to patients with: · Second- or third- degree AV block, or · Sinus node dysfunction unless these patients have a functioning artificial pacemaker [ see Warnings and Precautions (5.2) ] . Do not administer Regadenoson injection to patients with: · Second- or third- degree AV block, or · sinus node dysfunction unless the patients have a functioning artificial pacemaker ( 4 ).

DRUG INTERACTIONS No formal pharmacokinetic drug interacion studies have been conducted with regadenoson. Methylxanthines, e.g., caffeine, aminophylline and theophylline, interfere with the activity of regadenoson injection (7.1, 12.2 ). Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson injection (7.1, 10) . Dipyridamole may increase the activity of regadenoson injection. When possible, withhold dipyridamole for at least two days prior to regadenoson injection administration (7.1) . 7.1 Effects of Other Drugs on Regadenoson • Methylxanthines (e.g., caffeine, aminophylline and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of regadenoson [see Clinical Pharmacology ( 12.2) and Patient Counseling Information ( 17) ]. Patients should avoid consumption of any products containing methylxanthines as well as any drugs containing theophylline or aminophylline for at least 12 hours before regadenoson administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to regadenoson [see Overdosage ( 10 ) ]. • In clinical studies, regadenoson was administered to patients taking other cardioactive drugs (i.e., β- blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, and angiotensin receptor blockers) without reported adverse reactions or apparent effects on efficacy. • Dipyridamole may change the effects of regadenoson. When possible, withhold dipyridamole for at least two days prior to regadenoson administration. 7.2 Effect of Regadenoson on Other Drugs Regadenoson does not inhibit the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in human liver microsomes, indicating that it is unlikely to alter the pharmacokinetics of drugs metabolized by these cytochrome P450 enzymes. 7.1 Effects of Other Drugs on Regadenoson • Methylxanthines (e.g., caffeine, aminophylline and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of regadenoson [see Clinical Pharmacology ( 12.2) and Patient Counseling Information ( 17) ]. Patients should avoid consumption of any products containing methylxanthines as well as any drugs containing theophylline or aminophylline for at least 12 hours before regadenoson administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to regadenoson [see Overdosage ( 10 ) ]. • In clinical studies, regadenoson was administered to patients taking other cardioactive drugs (i.e., β- blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, and angiotensin receptor blockers) without reported adverse reactions or apparent effects on efficacy. • Dipyridamole may change the effects of regadenoson. When possible, withhold dipyridamole for at least two days prior to regadenoson administration. 7.2 Effect of Regadenoson on Other Drugs Regadenoson does not inhibit the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in human liver microsomes, indicating that it is unlikely to alter the pharmacokinetics of drugs metabolized by these cytochrome P450 enzymes.

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling. Myocardial Ischemia [see Warnings and Precautions ( 5.1 ) ] Sinoatrial and Atrioventricular Nodal Block [see Warnings and Precautions ( 5.2 ) ] Atrial Fibrillation/Atrial Flutter [see Warnings and Precautions ( 5.3 ) ] Hypersensitivity, Including Anaphylaxis [see Warnings and Precautions ( 5.4 ) ] Hypotension [see Warnings and Precautions ( 5.5 ) ] Hypertension [see Warnings and Precautions ( 5.6 ) ] Bronchoconstriction [see Warnings and Precautions ( 5.7 ) ] Seizure [see Warnings and Precautions ( 5.8 ) ] Cerebrovascular Accident (Stroke) [see Warnings and Precautions ( 5.9 ) ] The most common (incidence ≥ 5%) adverse reactions to regadenoson injection are dyspnea, headache, flushing, chest discomfort, dizziness, angina pectoris, chest pain, and nausea ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy's Laboratories Inc., at 1-888-375-3784 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. During clinical development, 1,651 patients were exposed to regadenoson, with most receiving 0.4 mg as a rapid (≤ 10 seconds) intravenous injection. Most of these patients received regadenoson in two clinical studies that enrolled patients who had no history of bronchospastic lung disease as well as no history of a cardiac conduction block of greater than first-degree AV block, except for patients with functioning artificial pacemakers. In these studies (Studies 1 and 2), 2,015 patients underwent myocardial perfusion imaging after administration of regadenoson (N = 1,337) or ADENOSCAN (N = 678). The population was 26–93 years of age (median 66 years), 70% male and primarily Caucasian (76% Caucasian, 7% African American, 9% Hispanic, 5% Asian). Table 1 shows the most frequently reported adverse reactions. Overall, any adverse reaction occurred at similar rates between the study groups (80% for the regadenoson group and 83% for the ADENOSCAN group). Aminophylline was used to treat the reactions in 3% of patients in the regadenoson group and 2% of patients in the ADENOSCAN group. Most adverse reactions began soon after dosing, and generally resolved within approximately 15 minutes, except for headache which resolved in most patients within 30 minutes. Table 1 Adverse Reactions in Studies 1 and 2 Pooled (Frequency ≥ 5%) REGADENOSON N = 1,337 ADENOSCAN N = 678 Dyspnea 28% 26% Headache 26% 17% Flushing 16% 25% Chest Discomfort 13% 18% Angina Pectoris or ST Segment Depression 12% 18% Dizziness 8% 7% Chest Pain 7% 10% Nausea 6% 6% Abdominal Discomfort 5% 2% Dysgeusia 5% 7% Feeling Hot 5% 8% ECG Abnormalities The frequency of rhythm or conduction abnormalities following regadenoson or ADENOSCAN is shown in Table 2 [see Warnings and Precautions ( 5.2 )]. Table 2 Rhythm or Conduction Abnormalities* in Studies 1 and 2 REGADENOSON N / N evaluable (%) ADENOSCAN N / N evaluable (%) Rhythm or conduction abnormalities† 332/1275 (26%) 192/645 (30%) Rhythm abnormalities 260/1275 (20%) 131/645 (20%) PACs 86/1274 (7%) 57/645 (9%) PVCs 179/1274 (14%) 79/645 (12%) First-degree AV block (PR prolongation > 220 msec) 34/1209 (3%) 43/618 (7%) Second-degree AV block 1/1209 (0.1%) 9/618 (1%) AV conduction abnormalities (other than AV blocks) 1/1209 (0.1%) 0/618 (0%) Ventricular conduction abnormalities 64/1152 (6%) 31/581 (5%) *12-lead ECGs were recorded before and for up to 2 hours after dosing. †includes rhythm abnormalities (PACs, PVCs, atrial fibrillation/flutter, wandering atrial pacemaker, supraventricular or ventricular arrhythmia) or conduction abnormalities, including AV block. Respiratory Abnormalities In a randomized, placebo-controlled trial of 999 patients with asthma (n = 532) or stable chronic obstructive pulmonary disease (n = 467), the overall incidence of pre-specified respiratory adverse reactions was greater in the regadenoson group compared to the placebo group (p < 0.001). Most respiratory adverse reactions resolved without therapy; a few patients received aminophylline or a short-acting bronchodilator. No differences were observed between treatment arms in the reduction of >15% from baseline at two-hours in FEV 1 (Table 3). Table 3 Respiratory Adverse Effects * Asthma Cohort Chronic Obstructive Pulmonary Disease (COPD) Cohort Regadenoson (N=356) Placebo (N=176) Regadenoson (N=316) Placebo (N=151) Overall Pre-specified Respiratory Adverse Reaction † 12.9% 2.3% 19.0% 4.0% Dyspnea 10.7% 1.1% 18.0% 2.6% Wheezing 3.1% 1.1% 0.9% 0.7% FEV 1 reduction >15% ‡ 1.1% 2.9% 4.2% 5.4% *All patients continued the use of their respiratory medications as prescribed prior to administration of regadenoson. †Patients may have reported more than one type of adverse reaction. Adverse reactions were collected up to 24 hours following drug administration. Pre-specified respiratory adverse reactions included dyspnea, wheezing, obstructive airway disorder, dyspnea exertional, and tachypnea. ‡Change from baseline at 2 hours. Renal Impairment In a randomized, placebo-controlled trial of 504 patients (regadenoson n=334 and placebo n=170) with a diagnosis or risk factors for coronary artery disease and NKFK/DOQI Stage III or IV renal impairment (defined as GFR 15-59 mL/min/1.73 m 2 ), no serious adverse events were reported through the 24-hour follow-up period. Inadequate Exercise Stress In an open-label, multi-center trial evaluating regadenoson administration following inadequate exercise stress, 1,147 patients were randomized into one of two groups. Each group underwent two regadenoson stress myocardial perfusion imaging (MPI) procedures. Group 1 received regadenoson 3 minutes following inadequate exercise in the first regadenoson stress (MPI 1). Group 2 rested 1 hour after inadequate exercise to allow hemodynamics to return to baseline prior to receiving regadenoson (MPI 1). Both groups returned for a second stress MPI 1-14 days later and received regadenoson without exercise (MPI 2). The most common adverse reactions are similar in type and incidence to those in Table 1 above for both Groups. The timing of the administration of regadenoson following inadequate exercise did not alter the common adverse reaction profile. Table 4 shows a comparison of cardiac events of interest for the two groups [see Warnings and Precautions ( 5.1 ) ]. The cardiac events were numerically higher in Group 1. Table 4 Cardiac Events of Interest in Inadequate Exercise Stress Study Cardiac Event* Group 1 / MPI 1 Regadenoson 3 minutes following exercise (N=575) Group 2 / MPI 1 Regadenoson 1 hour following exercise (N=567) 17 (3.0%) 3 (0.5%) Holter/12-Lead ECG Abnormality ST-T Depression (≥ 2 mm) 13 (2.3%) 2 (0.4%) ST-T Elevation (≥ 1 mm) 3 (0.5%) 1 (0.2%) Acute coronary syndrome 1 (0.2%) 0 Myocardial infarction 1 (0.2%) 0 *A clinically significant cardiac event was defined as any of the following events found on the Holter ECG/12-lead ECG within one hour after regadenoson administration: ventricular arrhythmias (sustained ventricular tachycardia, ventricular fibrillation, Torsade de Pointes, ventricular flutter); ST-T depression (≥ 2 mm); ST-T elevation (≥ 1 mm); AV block (2:1 AV block, AV Mobitz I, AV Mobitz II, complete heart block); sinus arrest > 3 seconds in duration Or a Treatment Emergent Adverse Event (TEAE) per the MedDRA SMQ (narrow Scope) for myocardial infarction Or a TEAE preferred term (PT) of angina unstable within 24 hours of regadenoson administration. 6.2 Post-Marketing Experience The following adverse reactions have been reported from worldwide marketing experience with regadenoson. Because these reactions are reported voluntarily from a population of uncertain size, it is not always po

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Regadenoson is a low affinity agonist (K i ≈ 1.3 µM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (K i > 16.5 µM), and weak, if any, affinity for the A 2B and A 3 adenosine receptors. Activation of the A 2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF). 12.2 Pharmacodynamics Coronary Blood Flow Regadenoson causes a rapid increase in CBF which is sustained for a short duration. In patients undergoing coronary catheterization, pulsed-wave Doppler ultrasonography was used to measure the average peak velocity (APV) of coronary blood flow before and up to 30 minutes after administration of regadenoson (0.4 mg, intravenously). Mean APV increased to greater than twice baseline by 30 seconds and decreased to less than twice the baseline level within 10 minutes [ see Clinical Pharmacology ( 12.3 ) ]. Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because regadenoson increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, regadenoson causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after regadenoson administration is therefore greater in areas perfused by normal relative to stenosed arteries. Effect of duration of injection A study in dogs compared the effects of intravenous injection of 2.5 µg/kg regadenoson (in 10 mL) over 10 seconds and 30 seconds on CBF. The duration of a two-fold increase in CBF was 97±14 seconds (n=6) and 221±20 seconds (n=4), respectively, for the 10 second and 30 second injections. The peak effects (i.e., maximal increase) on CBF after the 10 second and 30 second injections were 217±15% and 297±33% above baseline, respectively. The times to peak effect on CBF were 17±2 seconds and 27±6 seconds, respectively. Effect of Aminophylline Aminophylline (100 mg, administered by slow intravenous injection over 60 seconds) injected 1 minute after 0.4 mg regadenoson in patients undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to regadenoson as measured by pulsed-wave Doppler ultrasonography [ see Overdosage ( 10 ) ]. Effect of Caffeine Ingestion of caffeine decreases the ability to detect reversible ischemic defects. In a placebo-controlled, parallel group clinical study, patients with known or suspected myocardial ischemia received a baseline rest/stress MPI followed by a second stress MPI. Patients received caffeine or placebo 90 minutes before the second regadenoson stress MPI. Following caffeine administration (200 or 400 mg), the mean number of reversible defects identified was reduced by approximately 60%. This decrease was statistically significant [ see Drug Interactions ( 7.1 ) and Patient Counseling Information ( 17 ) ]. Hemodynamic Effects In clinical studies, the majority of patients had an increase in heart rate and a decrease in blood pressure within 45 minutes after administration of regadenoson. Maximum hemodynamic changes after regadenoson and Adenoscan in Studies 1 and 2 are summarized in Table 5. Table 5 Hemodynamic Effects in Studies 1 and 2 Vital Sign Parameter Regadenoson N = 1,337 Adenoscan N = 678 Heart Rate > 100 bpm 22% 13% Increase > 40 bpm 5% 3% Systolic Blood Pressure < 90 mm Hg 2% 3% Decrease > 35 mm Hg 7% 8% ≥ 200 mm Hg 1.9% 1.9% Increase ≥ 50 mm Hg 0.7% 0.8% ≥ 180 mm Hg and increase of ≥ 20 mm Hg from baseline 4.6% 3.2% Diastolic Blood Pressure < 50 mm Hg 2% 4% Decrease > 25 mm Hg 4% 5% ≥ 115 mm Hg 0.9% 0.9% Increase ≥ 30 mm Hg 0.5% 1.1% Hemodynamic Effects Following Inadequate Exercise In a clinical study, regadenoson was administered for MPI following inadequate exercise stress. More patients with regadenoson administration three minutes following inadequate exercise stress had an increase in heart rate and a decrease in systolic blood pressure compared with regadenoson administered at rest. The changes were not associated with any clinically significant adverse reactions. Maximum hemodynamic changes are presented in Table 6. Table 6 Hemodynamic Effects in Inadequate Exercise Stress Study Vital Sign Parameter Group 1 / MPI 1 Regadenoson 3 minutes following exercise (N=575) Group 2 / MPI 1 Regadenoson 1 hour following exercise (N=567) Heart Rate > 100 bpm 44% 31% Increase > 40 bpm 5% 16% Systolic Blood Pressure < 90 mm Hg 2% 4% Decrease > 35 mm Hg 29% 10% ≥ 200 mm Hg 0.9% 0.4% Increase ≥ 50 mm Hg 2% 0.4% ≥ 180 mm Hg and increase of ≥ 20 mm Hg from baseline 5% 2% Diastolic Blood Pressure < 50 mm Hg 3% 3% Decrease > 25 mm Hg 6% 5% ≥ 115 mm Hg 0.7% 0.4% Increase ≥ 30 mm Hg 2% 1% Respiratory Effects The A 2B and A 3 adenosine receptors have been implicated in the pathophysiology of bronchoconstriction in susceptible individuals (i.e., asthmatics). In in vitro studies, regadenoson has not been shown to have appreciable binding affinity for the A 2B and A 3 adenosine receptors. In a randomized, placebo-controlled clinical trial of 999 patients with a diagnosis, or risk factors for, coronary artery disease and concurrent asthma or COPD, the incidence of respiratory adverse reactions (dyspnea, wheezing) was greater with regadenoson compared to placebo. Moderate (2.5%) or severe (< 1%) respiratory reactions were observed more frequently in the regadenoson group compared to placebo [ see Adverse Reactions ( 6.1 ) ]. 12.3 Pharmacokinetics In healthy subjects, the regadenoson plasma concentration-time profile is multi-exponential in nature and best characterized by 3-compartment model. The maximal plasma concentration of regadenoson is achieved within 1 to 4 minutes after injection of regadenoson and parallels the onset of the pharmacodynamic response. The half-life of this initial phase is approximately 2 to 4 minutes. An intermediate phase follows, with a half-life on average of 30 minutes coinciding with loss of the pharmacodynamic effect. The terminal phase consists of a decline in plasma concentration with a half-life of approximately 2 hours [ see Clinical Pharmacology ( 12.2 ) ]. Within the dose range of 0.3–20 µg/kg in healthy subjects, clearance, terminal half-life or volume of distribution do not appear dependent upon the dose. A population pharmacokinetic analysis including data from subjects and patients demonstrated that regadenoson clearance decreases in parallel with a reduction in creatinine clearance and clearance increases with increased body weight. Age, gender, and race have minimal effects on the pharmacokinetics of regadenoson. Specific Populations Renally Impaired Patients: The disposition of regadenoson was studied in 18 patients with various degrees of renal function and in 6 healthy subjects. With increasing renal impairment, from mild (CLcr 50 to < 80 mL/min) to moderate (CLcr 30 to < 50 mL/min) to severe renal impairment (CLcr < 30 mL/min), the fraction of regadenoson excreted unchanged in urine and the renal clearance decreased, resulting in increased elimination half-lives and AUC values compared to healthy subjects (CLcr ≥ 80 mL/min). However, the maximum observed plasma concentrations as well as volumes of distribution estimates were similar across the groups. The plasma concentration-time profiles were not significantly altered in the early stages after dosing when most pharmacologic effects are observed. No dose adjustment is needed in patients with renal impairment. Patients with End Stage Renal Disease: The pharmacokinetics of regadenoson in patients on dialysis has not been assessed; however, in an in vitro study regadenoson was found to be dialyzable. Hepatically Impaired Patients: The influence of hepatic impairment on the pharmacokinetics of regadenoson has not been evaluated. Because greater than 55% of the dose is excreted in the urine as unchanged drug and factors that decrease clearance do not affect the plasma concentration in t