ECG Abnormalities

The frequency of rhythm or conduction abnormalities following regadenoson or adenosine 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 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 (MPI 1). Both groups returned for a second stress MPI 1 to 14 days later and received regadenoson 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 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.

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.

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.

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.

Coronary Blood Flow

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

Hemodynamic Effects Following Inadequate Exercise

In a clinical study, regadenoson was administered for MPI following inadequate exercise stress. More patients with regadenoson administration three minutes following inadequate exercise stress had an increase in heart rate and a decrease in systolic blood pressure compared with regadenoson administered at rest. The changes were not associated with any clinically significant adverse reactions. Maximum hemodynamic changes are presented in Table 6.

Table 6 Hemodynamic Effects in Inadequate Exercise Stress Study

Respiratory Effects

The A2B and A3 adenosine receptors have been implicated in the pathophysiology of bronchoconstriction in susceptible individuals (i.e., asthmatics). In in vitro studies, regadenoson has not been shown to have appreciable binding affinity for the A2B and A3 adenosine receptors.

In a randomized, placebo-controlled clinical trial of 999 patients with a diagnosis, or risk factors for, coronary artery disease and concurrent asthma or COPD, the incidence of respiratory adverse reactions (dyspnea, wheezing) was greater with regadenoson compared to placebo. Moderate (2.5%) or severe (<1%) respiratory reactions were observed more frequently in the regadenoson group compared to placebo [see Adverse Reactions (6.1)].

Specific 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 to 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.

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.