6 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 LEXISCAN are dyspnea, headache, flushing, chest discomfort, dizziness, angina pectoris, chest pain, and nausea (6). To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 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 LEXISCAN, with most receiving 0.4 mg as a rapid (≤ 10 seconds) intravenous injection. Most of these patients received LEXISCAN 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 LEXISCAN (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 LEXISCAN group and 83% for the ADENOSCAN group). Aminophylline was used to treat the reactions in 3% of patients in the LEXISCAN 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%) LEXISCAN 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 LEXISCAN or ADENOSCAN is shown in Table 2 [see Warnings and Precautions (5.2)]. Table 2 Rhythm or Conduction Abnormalities12-lead ECGs were recorded before and for up to 2 hours after dosing. in Studies 1 and 2 LEXISCAN N / N evaluable (%) ADENOSCAN N / N evaluable (%) Rhythm or conduction abnormalitiesincludes rhythm abnormalities (PACs, PVCs, atrial fibrillation/flutter, wandering atrial pacemaker, supraventricular or ventricular arrhythmia) or conduction abnormalities, including AV block. 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%) 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 LEXISCAN 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 FEV1 (Table 3). Table 3 Respiratory Adverse EffectsAll patients continued the use of their respiratory medications as prescribed prior to administration of LEXISCAN. Asthma Cohort Chronic Obstructive Pulmonary Disease (COPD) Cohort LEXISCAN (N=356) Placebo (N=176) LEXISCAN (N=316) Placebo (N=151) Overall Pre-specified Respiratory Adverse ReactionPatients 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. 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% FEV1 reduction >15%Change from baseline at 2 hours. 1.1% 2.9% 4.2% 5.4% Renal Impairment In a randomized, placebo-controlled trial of 504 patients (LEXISCAN 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 m2), no serious adverse events were reported through the 24-hour follow-up period. Inadequate Exercise Stress In an open-label, multi-center trial evaluating LEXISCAN administration following inadequate exercise stress, 1,147 patients were randomized into one of two groups. Each group underwent two LEXISCAN stress myocardial perfusion imaging (MPI) procedures. Group 1 received LEXISCAN 3 minutes following inadequate exercise in the first LEXISCAN stress (MPI 1). Group 2 rested 1 hour after inadequate exercise to allow hemodynamics to return to baseline prior to receiving LEXISCAN (MPI 1). Both groups returned for a second stress MPI 1-14 days later and received LEXISCAN 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 LEXISCAN 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 EventA 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. Group 1 / MPI 1 LEXISCAN 3 minutes following exercise (N=575) Group 2 / MPI 1 LEXISCAN 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 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 possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular Myocardial infarction, cardiac arrest, ventricular arrhythmias, supraventricular tachyarrhythmias including atrial fibrillation with rapid ventricular response (new-onset or recurrent), atrial flutter, heart block (including third-degree block), asystole, marked hypertension, symptomatic hypotension in association with transient ischemic attack, acute coronary syndrome (ACS), seizures and syncope [see Warnings and Precautions (5.1), (5.2), (5.3), (5.5), (5.6) and (5.8)] have been reported. Some events required intervention with fluids and/or aminophylline [see Overdosage (10)]. QTc prolongation shortly after LEXISCAN administration has been reported. Central Nervous System Tremor, seizure, transient ischemic attack, and cerebrovascular accident including intracranial hemorrhage [see Warnings and Precautions (5.8) and (5.9)]. Gastrointestinal Abdominal pain, occasionally severe, has been reported a few minutes after LEXISCAN administration, in association with nausea, vomiting, or myalgias; administration of aminophylline, an adenosine antagonist, appeared to lessen the pain. Diarrhea and fecal incontinence have also been reported following LEXISCAN administration. Hypersensitivity Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria, rashes have occurred and have required treatment including resuscitation [see Warnings and Precautions (5.4)]. Musculoskeletal Musculoskeletal pain has occurred, typically 10-20 minutes after LEXISCAN administration; the pain was occasionally severe, localized in the arms and lower back and extended to the buttocks and lower legs bilaterally. Administration of aminophylline appeared to lessen the pain. Respiratory Respiratory arrest, dyspnea and wheezing have been reported following LEXISCAN administration.