5.1 Myocardial Ischemia

Fatal and nonfatal myocardial infarction, 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 postmarketing 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 min 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 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 subjects were exposed to Regadenoson injection, with most receiving 0.4 mg as a rapid (≤ 10 seconds) intravenous injection. Most of these subjects 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– 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.

Table 1 Adverse Reactions in Studies 1 and 2 Pooled (Frequency ≥ 5%)

ECG Abnormalities:
The frequency of rhythm or conduction abnormalities following Regadenoson injection or ADENOSCAN is shown in Table 2 [see Warnings and Precautions (5.2)]. 

Table 2 Rhythm or Conduction Abnormalities* in Studies 1 and 2

* 12-lead ECG s were recorded before and for up to 2 hrs after dosing
# includes rhythm abnormalities (PACs, PVCs, atrial fibrillation/flutter, wandering atrial pacemaker, supraventricular or ventricular arrhythmia) or conduction abnormalities, including AV block

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, 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 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

Risk Summary

There are no available data on Regadenoson injection 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 Regadenoson injection.

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)].

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

Coronary Blood Flow
Regadenoson injection 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 injection increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Regadenoson injection causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after Regadenoson injection 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 injection in subjects undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to Regadenoson injection 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 injection 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 injection. Maximum hemodynamic changes after Regadenoson injection and Adenoscan in Studies 1 and 2 are summarized in Table 5.

Table 5 Hemodynamic Effects in Studies 1 and 2

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 0.3–20 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.

Special 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 the early stages after dosing when clinically meaningful pharmacologic effects are observed, no dose adjustment is needed in patients with hepatic impairment.

Geriatric Patients: Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of regadenoson. No dose adjustment is needed in elderly patients.

Metabolism
The metabolism of regadenoson is unknown in humans. Incubation with rat, dog, and human liver microsomes as well as human hepatocytes produced no detectable metabolites of regadenoson.

Excretion
In healthy volunteers, 57% of the regadenoson dose is excreted unchanged in the urine (range 19–77%), with an average plasma renal clearance around 450 mL/min, i.e., in excess of the glomerular filtration rate. This indicates that renal tubular secretion plays a role in regadenoson elimination.

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

Cardiomyopathy:
Minimal cardiomyopathy (myocyte necrosis and inflammation) was observed in rats following single-dose administration of regadenoson. Increased incidence of minimal cardiomyopathy was observed on day 2 in males at doses of 0.08, 0.2 and 0.8 mg/kg (1/5, 2/5, and 5/5) and in females (2/5) at 0.8 mg/kg. In a separate study in male rats, the mean arterial pressure was decreased by 30 to 50% of baseline values for up to 90 minutes at regadenoson doses of 0.2 and 0.8 mg/kg, respectively. No cardiomyopathy was noted in rats sacrificed 15 days following single administration of regadenoson. The mechanism of the cardiomyopathy induced by regadenoson was not elucidated in this study but was associated with the hypotensive effects of regadenoson. Profound hypotension induced by vasoactive drugs is known to cause cardiomyopathy in rats.

Local Irritation:

Intravenous administration of Regadenoson injection to rabbits resulted in perivascular hemorrhage, vein vasculitis, inflammation, thrombosis and necrosis, with inflammation and thrombosis persisting through day 8 (last observation day). Perivascular administration of Regadenoson injection to rabbits resulted in hemorrhage, inflammation, pustule formation and epidermal hyperplasia, which persisted through day 8 except for the hemorrhage which resolved. Subcutaneous administration of Regadenoson injection to rabbits resulted in hemorrhage, acute inflammation, and necrosis; on day 8 muscle fiber regeneration was observed.