5.1 Myocardial Ischemia

Fatal and nonfatal myocardial infarction (MI), ventricular arrhythmias, and cardiac arrest have occurred following regadenoson 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 regadenoson injection. Cardiac resuscitation equipment and trained staff should be available before administering regadenoson injection. 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 injection [see Overdosage (10)].

5.2 Sinoatrial and Atrioventricular 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 requiring intervention. In clinical trials first-degree AV block (PR prolongation > 220 msec) developed in 3% of patients within 2 hours of regadenoson injection administration; transient second-degree AV block with one dropped beat was observed in one patient receiving regadenoson injection. In post-marketing experience, third-degree heart block and asystole within minutes of regadenoson injection 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 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 regadenoson injection, 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 injection 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 injection, 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 injection 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 injection, may cause dyspnea, bronchoconstriction, and respiratory compromise. Appropriate bronchodilator therapy and resuscitative measures should be available prior to and following regadenoson injection administration [see Adverse Reactions (6.1), Clinical Pharmacology (12.2), Overdosage (10) and Patient Counseling Information (17)].

5.8 Seizure

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

5.9 Cerebrovascular Accident (Stroke)

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

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 injection, with most receiving 0.4 mg as a rapid (≤ 10 seconds) intravenous injection. Most of these patients received regadenoson injection 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 injection (N = 1,337) or Adenoscan (N = 678). The population was 26 to 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 injection group and 83% for the Adenoscan group). Aminophylline was used to treat the reactions in 3% of patients in the regadenoson injection 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.

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 regadenoson injection 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 regadenoson injection 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 regadenoson injection administration.

Hypersensitivity

Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria, and rashes have occurred and have required treatment including resuscitation [see Warnings and Precautions (5.4)].

Musculoskeletal

Musculoskeletal pain has occurred, typically 10 to 20 minutes after regadenoson injection 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 regadenoson injection administration.

7.1 Effects of Other Drugs on Regadenoson Injection

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

7.2 Effect of Regadenoson Injection 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

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the 1,337 patients receiving regadenoson injection 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)].

Aminophylline to Reverse Effects

Methylxanthines, such as caffeine, aminophylline, and theophylline, are competitive adenosine receptor antagonists and aminophylline has been used to terminate persistent pharmacodynamic effects. Aminophylline may be administered in doses ranging from 50 mg to 250 mg by slow intravenous injection (50 mg to 100 mg over 30 to 60 seconds). Methylxanthine use is not recommended in patients who experience a seizure in association with regadenoson injection administration [see Warnings and Precautions (5.8)].

12.1 Mechanism of Action

Regadenoson is a low affinity agonist (Ki ≈ 1.3 µM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 µM), and weak, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF).

12.2 Pharmacodynamics

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 injection 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 to 20 mcg/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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Regadenoson was negative in the Ames bacterial mutation assay, chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and mouse bone marrow micronucleus assay.

Long-term animal studies have not been conducted to evaluate regadenoson injection's carcinogenic potential or potential effects on fertility.

13.2 Animal Toxicology and/or Pharmacology

Agreement between Regadenoson Injection and Adenoscan

The efficacy and safety of regadenoson injection were determined relative to Adenoscan in two randomized, double-blind studies (Studies 1 and 2) in 2,015 patients with known or suspected coronary artery disease who were indicated for pharmacologic stress MPI. A total of 1,871 of these patients had images considered valid for the primary efficacy evaluation, including 1,294 (69%) men and 577 (31%) women with a median age of 66 years (range 26 to 93 years of age). Each patient received an initial stress scan using Adenoscan (6-minute infusion using a dose of 0.14 mg/kg/min, without exercise) with a radionuclide gated SPECT imaging protocol. After the initial scan, patients were randomized to either regadenoson injection or Adenoscan and received a second stress scan with the same radionuclide imaging protocol as that used for the initial scan. The median time between scans was 7 days (range of 1 to 104 days).

The most common cardiovascular histories included hypertension (81%), CABG, PTCA or stenting (51%), angina (63%), and history of myocardial infarction (41%) or arrhythmia (33%); other medical history included diabetes (32%) and COPD (5%). Patients with a recent history of serious uncontrolled ventricular arrhythmia, myocardial infarction, or unstable angina, a history of greater than first-degree AV block, or with symptomatic bradycardia, sick sinus syndrome, or a heart transplant were excluded. A number of patients took cardioactive medications on the day of the scan, including β-blockers (18%), calcium channel blockers (9%), and nitrates (6%). In the pooled study population, 68% of patients had 0 to 1 segments showing reversible defects on the initial scan, 24% had 2 to 4 segments, and 9% had ≥ 5 segments.

Comparison of the images obtained with regadenoson injection to those obtained with Adenoscan was performed as follows. Using the 17-segment model, the number of segments showing a reversible perfusion defect was calculated for the initial Adenoscan study and for the randomized study obtained using regadenoson injection or Adenoscan. The agreement rate for the image obtained with regadenoson injection or Adenoscan relative to the initial Adenoscan image was calculated by determining how frequently the patients assigned to each initial Adenoscan category (0 to 1, 2 to 4, 5 to 17 reversible segments) were placed in the same category with the randomized scan. The agreement rates for regadenoson injection and Adenoscan were calculated as the average of the agreement rates across the three categories determined by the initial scan. Studies 1 and 2 each demonstrated that regadenoson injection is similar to Adenoscan in assessing the extent of reversible perfusion abnormalities (Table 7).

Use of Regadenoson Injection in Patients with Inadequate Exercise Stress

The efficacy and safety of regadenoson injection administered 3 minutes (Group 1) or 1 hour (Group 2) following inadequate exercise stress were evaluated in an open-label randomized, multi-center, non-inferiority study. Adequate exercise was defined as ≥ 85% maximum predicted heart rate and ≥ 5 METS. SPECT MPI was performed 60 to 90 minutes after regadenoson injection administration in each group (MPI 1). Patients returned 1 to 14 days later to undergo a second stress MPI with regadenoson injection without exercise (MPI 2).

All patients were referred for evaluation of coronary artery disease. Of the 1,147 patients randomized, a total of 1,073 patients received regadenoson injection and had interpretable SPECT scans at all visits; 538 in Group 1 and 535 in Group 2. The median age of the patients was 62 years (range 28 to 90 years) and included 633 (59%) men and 440 (41%) women.

Images from MPI 1 and MPI 2 for the two groups were compared for presence or absence of perfusion defects. The level of agreement between the MPI 1 and the MPI 2 reads in Group 1 was similar to the level of agreement between MPI 1 and MPI 2 reads in Group 2. However, two patients receiving regadenoson injection 3 minutes following inadequate exercise experienced a serious cardiac adverse reaction. No serious cardiac adverse reactions occurred in patients receiving regadenoson injection 1 hour following inadequate exercise stress [see Adverse Reactions (6.1), Clinical Pharmacology (12.2)].

Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature].

Drug Interaction

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 Warnings and Precautions (5.8) and Clinical Pharmacology (12.2)].

Cardiovascular

Advise patients that they may be at increased risk of fatal and nonfatal heart attacks, abnormal heart rhythms, cardiac arrest, significant increase or decrease in blood pressure, or cerebrovascular accidents (stroke) with the use of regadenoson injection [see Warnings and Precautions (5.1), (5.3), (5.5), (5.6) and (5.9)].

Hypersensitivity

Inform patients that allergic reactions have been reported with regadenoson injection. Advise patients how to recognize such a reaction and when to seek medical attention [see Warnings and Precautions (5.4)].

Respiratory

Advise patients with COPD or asthma about the need for administration of pre- and post-study bronchodilator therapy and to call their clinician if they experience any shortness of breath or difficulty breathing following an MPI study with regadenoson injection [see Warnings and Precautions (5.7)].

Seizures

Advise patients that they may be at increased risk of seizures. Question patients about a history of seizures [see Warnings and Precautions (5.8)].

Lactation

Advise a woman to pump and discard breast milk for 10 hours after regadenoson injection administration [see Use in Specific Populations (8.2)].