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. 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 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 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, 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 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 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)].

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 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 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.

ECG Abnormalities

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

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 FEV1 (Table 3).

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 to 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 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 injection 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 injection (MPI 1). Both groups returned for a second stress MPI 1 to 14 days later and received regadenoson injection 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 injection 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

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 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 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 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 to 20 minutes after regadenoson 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 administration.

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.

8.1 Pregnancy

Risk Summary

There are no available data on regadenoson 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 to 4% and 15 to 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 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 mcgM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 mcgM), 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 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'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 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 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 to rabbits resulted in hemorrhage, acute inflammation, and necrosis; on day 8 muscle fiber regeneration was observed.

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 [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. 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 [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 administration [see Use in Specific Populations (8.2)]. 

All registered trademarks in this document are the property of their respective owners.

Rx Only

Revised:  07/2022

NovaPlus is a registered trademark of Vizient, Inc.