Regadenoson

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 ).

• Single-dose pre-filled syringe: clear, colorless solution containing regadenoson 0.4 mg/5 mL (0.08 mg/mL).
• Injection: Single-dose pre-filled syringe: 0.4 mg/5 mL (0.08 mg/mL) ( 3 ).

Do not administer LEXISCAN 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 LEXISCAN to patients with:
• Second- or third-degree AV block, or
• sinus node dysfunction unless the patients have a functioning artificial pacemaker ( 4 ).

• 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 LEXISCAN, 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 LEXISCAN, 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 LEXISCAN, 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 LEXISCAN, 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. LEXISCAN 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 LEXISCAN ( 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 LEXISCAN injection. 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 LEXISCAN. Cardiac resuscitation equipment and trained staff should be available before administering LEXISCAN. 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 LEXISCAN occur, consider the use of aminophylline, an adenosine antagonist, to shorten the duration of increased coronary blood flow induced by LEXISCAN [ see Overdosage ( 10 ) ].

5.2 Sinoatrial and Atrioventricular Nodal Block Adenosine receptor agonists, including LEXISCAN, 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 LEXISCAN administration; transient second-degree AV block with one dropped beat was observed in one patient receiving LEXISCAN. In post-marketing experience, third-degree heart block and asystole within minutes of LEXISCAN 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 LEXISCAN injection [ 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 LEXISCAN, 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 LEXISCAN 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 LEXISCAN, 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 LEXISCAN 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 LEXISCAN, may cause dyspnea, bronchoconstriction, and respiratory compromise. Appropriate bronchodilator therapy and resuscitative measures should be available prior to and following LEXISCAN administration [ see Adverse Reactions ( 6.1 ) , Clinical Pharmacology ( 12.2 ) , Overdosage ( 10 ) and Patient Counseling Information ( 17 ) ].

5.8 Seizure LEXISCAN may lower the seizure threshold; obtain a seizure history. New-onset or recurrence of convulsive seizures has occurred following LEXISCAN injection. Some seizures are prolonged and require emergent anticonvulsive management. Aminophylline may increase the risk of seizures associated with LEXISCAN injection. Methylxanthine use is not recommended in patients who experience a seizure in association with LEXISCAN administration.

5.9 Cerebrovascular Accident (Stroke) Hemorrhagic and ischemic cerebrovascular accidents have occurred. Hemodynamic effects of LEXISCAN including hypotension or hypertension may be associated with these adverse reactions [ see Warnings and Precautions ( 5.5 ) and ( 5.6 ) ].

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 Abnormalities 12-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 abnormalities includes 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 FEV 1 ( Table 3 ). Table 3 Respiratory Adverse Effects All 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 Reaction 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. 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% 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 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 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 Event 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. 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. […]

No formal pharmacokinetic drug interaction studies have been conducted with LEXISCAN.

• Methylxanthines, e.g., caffeine, aminophylline and theophylline, interfere with the activity of LEXISCAN ( 7.1 , 12.2 ).
• Aminophylline may be used to attenuate severe and/or persistent adverse reactions to LEXISCAN ( 7.1 , 10 ).
• Dipyridamole may increase the activity of LEXISCAN. When possible, withhold dipyridamole for at least two days prior to LEXISCAN administration ( 7.1 ).

7.1 Effects of Other Drugs on LEXISCAN

• Methylxanthines (e.g., caffeine, aminophylline and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of LEXISCAN [ 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 LEXISCAN administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to LEXISCAN [ see Overdosage ( 10 ) ].
• In clinical studies, LEXISCAN 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 LEXISCAN. When possible, withhold dipyridamole for at least two days prior to LEXISCAN administration.

7.2 Effect of LEXISCAN 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.

8.1 Pregnancy Risk Summary There are no available data on LEXISCAN use in pregnant women to inform a drug-associated risk. In animal reproduction studies, adverse developmental outcomes were observed with the administration of regadenoson to pregnant rats and rabbits during organogenesis only at doses that produced maternal toxicity ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Reproductive studies in rats showed that regadenoson doses 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area caused reduced fetal body weights and significant ossification delays in fore- and hind limb phalanges and metatarsals; maternal toxicity also occurred at these doses. Skeletal variations were increased in all treated groups. In rabbits, maternal toxicity occurred at regadenoson doses administered during organogenesis at 4 times the MRHD; however, there were no teratogenic effects in offspring at this dose. At higher doses, 12 and 20 times the MRHD, maternal toxicity occurred along with increased embryo-fetal loss and fetal malformations.

8.2 Lactation Risk Summary There is no information on the presence of regadenoson in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential risk of serious cardiac reactions in the breastfed infant, advise the nursing mother to pump and discard breast milk for 10 hours after administration of LEXISCAN.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Of the 1,337 patients receiving LEXISCAN in Studies 1 and 2, 56% were 65 years of age and over and 24% were 75 years of age and over. Older patients ( > 75 years of age) had a similar adverse event profile compared to younger patients (< 65 years of age), but had a higher incidence of hypotension (2% vs. ≤ 1%).

8.6 Renal Impairment No dose adjustment is needed in patients with renal impairment including patients with end stage renal disease and/or dependent on dialysis [ see Pharmacokinetics ( 12.3 ) ].

Regadenoson is a low affinity agonist (K i ≈ 1.3 µM) for the A 2A adenosine receptor, with at least 10-fold lower affinity for the A 1 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).