Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: GE Healthcare AS, Nycoveien 1, NO-0485, Oslo, Norway
Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations
ATC code: C01EB21
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 very low, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor produces coronary vasodilation and increases coronary blood flow (CBF). Despite low affinity for the A2A adenosine receptor, regadenoson has high potency for increasing coronary conductance in rat and guinea pig isolated hearts, with EC50 values of 6.4 nM and 6.7-18.6 nM, respectively. Regadenoson shows selectivity (≥215-fold) for increasing coronary conductance (A2A-mediated response) relative to slowing of cardiac AV nodal conduction (A1-mediated response) as measured by AV conduction time (rat heart) or the S-H interval (guinea pig heart). Regadenoson preferentially increases blood flow in coronary relative to peripheral (forelimb, brain, pulmonary) arterial vascular beds in the anaesthetised dog.
Regadenoson causes a rapid increase in CBF which is sustained for a short duration. In patients undergoing coronary catheterisation, pulsed-wave Doppler ultrasonography was used to measure the average peak velocity (APV) of CBF before and up to 30 minutes after administration of regadenoson (400 micrograms, intravenously). Mean APV increased to greater than twice baseline by 30 seconds and decreased to less than half of the maximal effect within 10 minutes (see section 5.2). 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. Myocardial radiopharmaceutical uptake after regadenoson administration is therefore greater in areas perfused by normal relative to stenosed arteries. The same applies to the FFR measurement where the maximal myocardial blood flow is decreased in presence of severe coronary artery stenosis.
The majority of patients experience a rapid increase in heart rate. The greatest mean change from baseline (21 bpm) occurs approximately 1 minute after administration of regadenoson. Heart rate returns to baseline within 10 minutes. Systolic blood pressure and diastolic blood pressure changes were variable, with the greatest mean change in systolic pressure of −3 mmHg and in diastolic pressure of −4 mm Hg approximately 1 minute after regadenoson administration. An increase in blood pressure has been observed in some patients (maximum systolic blood pressure of 240 mm Hg and maximum diastolic blood pressure of 138 mm Hg).
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 been shown to have little binding affinity for the A2B and A3 adenosine receptors. The incidence of a FEV1 reduction >15% from baseline after regadenoson administration was assessed in three randomised, controlled clinical studies. In the first study in 49 patients with moderate to severe COPD, the rate of FEV1 reduction >15% from baseline was 12% and 6% following regadenoson and placebo dosing, respectively (p=0.31). In the second study in 48 patients with mild to moderate asthma who had previously been shown to have bronchoconstrictive reactions to adenosine monophosphate, the rate of FEV1 reduction >15% from baseline was the same (4%) following both regadenoson and placebo dosing. In the third study in 1009 patients with mild or moderate asthma (n=537) and moderate or severe COPD (n=472) the incidence of FEV1 reduction >15% from baseline was 1.1% and 2.9% in patients with asthma (p=0.15) and 4.2% and 5.4% in patients with COPD (p=0.58) following regadenoson and placebo dosing, respectively. In the first and second studies, dyspnoea was reported as an adverse reaction following regadenoson dosing (61% for patients with COPD; 34% for patients with asthma) while no subjects experienced dyspnoea following placebo dosing. In the third study dyspnoea was reported more frequently following regadenoson (18% for patients with COPD; 11% for patients with asthma) than placebo, but at a lower rate than reported during clinical development (see Section 4.8). A relationship between increased severity of disease and the increased incidence of dyspnoea was apparent in patients with asthma, but not in patients with COPD. The use of bronchodilator therapy for symptoms was not different between regadenoson and placebo. Dyspnoea did not correlate with a decrease in FEV1.
In the measurement of FFR, the time to peak maximum hyperaemia was 30±13 seconds. The mean duration of hyperaemic plateau was 163 (±169) seconds and maximum hyperaemia lasted at least 19 seconds in 90% of patients, however, in the individual patient the duration of hyperaemia varied between 10 seconds to more than 10 minutes. Hyperaemia may fluctuate between sub-maximum and maximum until it slowly vanishes. The 10-second window of steady state hyperaemia can be too short for performing extensive pressure pullback recordings to assess complex or diffuse coronary artery disease. Repeat dosing within 10 minutes – except in patients where the duration of hyperaemia lasted for more than 10 minutes – caused a similar effect on peak and duration of maximum hyperaemia.
Clinical studies have demonstrated the efficacy and safety of regadenoson in patients indicated for pharmacologic stress radionuclide MPI and for the measurement of FFR.
The efficacy and safety of regadenoson for pharmacologic stress radionuclide MPI were determined relative to adenosine in two randomised, double-blind studies (ADVANCE MPI 1 and ADVANCE MPI 2) in 2,015 patients with known or suspected coronary artery disease who were referred for a clinically-indicated 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 26-93 years of age). Each patient received an initial stress scan using adenosine (6-minute infusion using a dose of 0.14 mg/kg/min, without exercise) with a radionuclide gated SPECT (single photon emission computed tomography) imaging protocol. After the initial scan, patients were randomised to either regadenoson or adenosine, 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 1-104 days).
The most common cardiovascular histories included hypertension (81%), coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty (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 medicinal products on the day of the scan, including β-blockers (18%), calcium channel blockers (9%), and nitrates (6%).
Comparison of the images obtained with regadenoson to those obtained with adenosine was performed as follows. Using the 17-segment model, the number of segments showing a reversible perfusion defect was calculated for the initial adenosine study and for the randomised study obtained using regadenoson or adenosine. In the pooled study population, 68% of patients had 0-1 segments showing reversible defects on the initial scan, 24% had 2-4 segments, and 9% had ≥5 segments. The agreement rate for the image obtained with regadenoson or adenosine relative to the initial adenosine image was calculated by determining how frequently the patients assigned to each initial adenosine category (0-1, 2-4, 5-17 reversible segments) were placed in the same category with the randomised scan. The agreement rates for regadenoson and adenosine were calculated as the average of the agreement rates across the three categories determined by the initial scan. The ADVANCE MPI 1 and ADVANCE MPI 2 studies, individually and combined, demonstrated that regadenoson is similar to adenosine in assessing the extent of reversible perfusion abnormalities:
| ADVANCE MPI 1 (n=1,113) | ADVANCE MPI 2 (n=758) | Combined Studies (n=1,871) | |
|---|---|---|---|
| Adenosine – Adenosine Agreement Rate (± SE) | 61 ± 3% | 64 ± 4% | 62 ± 3% |
| Number of Patients (n) | 372 | 259 | 631 |
| Adenosine – regadenoson Agreement Rate (± SE) | 62 ± 2% | 63 ± 3% | 63 ± 2% |
| Number of Patients (n) | 741 | 499 | 1,240 |
| Rate Difference (regadenoson – Adenosine) (± SE) | 1 ± 4% | -1 ± 5% | 0 ± 3% |
| 95% Confidence Interval | -7.5, 9.2% | -11.2, 8.7% | -6.2, 6.8% |
In ADVANCE MPI 1 and ADVANCE MPI 2, the Cicchetti-Allison and Fleiss-Cohen weighted kappas of the median score of three blinded readers with respect to ischaemia size category (not counting segments with normal rest uptake and mild/equivocal reduction in stress uptake as ischaemic) for the combined studies of regadenoson with the adenosine scan were moderate, 0.53 and 0.61, respectively; as were the weighted kappas of two consecutive adenosine scans, 0.50 and 0.55, respectively.
In the EXERRT trial the efficacy and safety of regadenoson was evaluated in patients with suboptimal Exercise Stress in an open-label randomized, multi-center, non-inferiority study when regadenoson administered either at 3 minutes during recovery (exercise with regadenoson) or at rest 1 hour later (regadenoson only).
All 1404 patients initially had a baseline MPI scan at rest in accordance with ASNC 2009 guidelines.
Patients initiated exercise using a standard or modified Bruce protocol. Patients who did not achieve ≥85% maximum predicted heart rate (MPHR) and/or ≥5 METS (metabolic equivalents), transitioned into a 3-5 minutes walking recovery where during the first 3 minutes of recovery, patients were randomized 1:1.
Therefore, 1147 patients were randomized in two groups: 578 patients from the exercise with regadenoson group and 569 from the regadenoson only group to either 3 minutes recovery (for the exercise with regadenoson group) or at rest 1 hour later (for the regadenoson only group).
Patients from both groups (exercise with regadenoson and regadenoson only) underwent a SPECT Myocardial Perfusion Imaging (MPI) at 60-90 minutes post-regadenoson administration.
The baseline MPI scan at rest, and the MPI scans for the exercise with regadenoson and regadenoson only groups constituted the MPI 1 phase.
Subsequentially, patients from both groups, returned 1-14 days later, to undergo a second stress MPI regadenoson study without exercise. The baseline MPI scans at rest and those without exercise at 1-14 days later from both groups, constituted the MPI 2 phase.
The images from MPI 1 and MPI 2 were compared for presence or absence of perfusion defects. The level of agreement between the MPI 1 (exercise with regadenoson) and the MPI 2 reads was similar to the level of agreement between MPI 1 (regadenoson only) and MPI 2 reads.
For two patients from the exercise with regadenoson group, a serious cardiac adverse reaction was reported. Upon case review, both patients, experienced ischemic symptoms and ECG changes during exercise or recovery prior to regadenoson administration. No serious cardiac adverse reactions occurred in patients receiving regadenoson 1 hour following inadequate exercise stress.
For the measurement of FFR, five independent studies have been conducted. A total of 249 patients, who were clinically indicated to undergo coronary angiography with invasive measurement of FFR, received regadenoson, with 88 of those patients receiving regadenoson twice. FFR was measured after IV infusion of adenosine and IV injection of regadenoson (400 μg). Adenosine was administered first, followed by regadenoson as its hyperaemia may last unpredictably and the measured FFR values were compared.
The most common cardiovascular conditions were patients with a medical history of hypertension, dyslipidemia/hypercholesterolemia, diabetes mellitus, smoking, prior PCI and prior MI.
For FFR measurement, a diagnosis of inducible ischemia was made according to the measurement of FFR of 0.8 (>0.8 represents the absence of inducible ischemia vs ≤0.8 representing the presence of inducible ischemia). Adenosine was treated as a gold standard to estimate sensitivity, specificity, and the proportion of accuracy.
| Study | Sensitivity | Specificity | Classification agreement Cohen’s kappa |
|---|---|---|---|
| Stolker et al. 2015 (n=149) | 98% | 97% | 0.94 |
| van Nunen et al. 2015 (n=98) | 98% | 95% | 0.94 |
Aminophylline (100 mg, administered by slow intravenous injection over 60 seconds) injected 1 minute after 400 micrograms regadenoson in subjects undergoing cardiac catheterisation, was shown to shorten the duration of the coronary blood flow response to regadenoson as measured by pulsed-wave Doppler ultrasonography. Aminophylline has been used to attenuate adverse reactions to regadenoson (see section 4.4).
In a study of adult patients undergoing pharmacological stress radionuclide MPI with regadenoson , randomized to placebo (n=66) or caffeine (200 mg, n=70 or 400 mg, n=71) administered 90 minutes before the test, caffeine compromised the diagnostic accuracy of detecting reversible perfusion defects (p<0.001). There was no statistical difference between 200 mg and 400 mg caffeine with regadenoson. Also, there was no apparent effect of 200 mg or 400 mg of caffeine on regadenoson plasma concentrations.
In ADVANCE MPI 1 and ADVANCE MPI 2, the following pre-specified safety and tolerability endpoints comparing regadenoson to adenosine achieved statistical significance: (1) a summed score of both the presence and severity of the symptom groups of flushing, chest pain, and dyspnoea was lower with regadenoson (0.9 ± 0.03) than with adenosine (1.3 ± 0.05); and (2) the symptom groups of flushing (21% vs 32%), chest pain (28% vs 40%), and ‘throat, neck or jaw pain’ (7% vs 13%) were less frequent with regadenoson; the incidence of headache (25% vs 16%) was more frequent with regadenoson.
The European Medicines Agency has deferred the obligation to submit the results of studies with regadenoson in one or more subsets of the paediatric population with myocardial perfusion disturbances (see section 4.2 for information on paediatric use).
Regadenoson is administered by intravenous injection for pharmacologic stress radionuclide MPI. The regadenoson plasma concentration-time profile in healthy volunteers is multi-exponential in nature and best characterised 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 (see section 5.1). 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. Within the dose range of 0.003-0.02 mg/kg (or approximately 0.18-1.2 mg) in healthy subjects, clearance, terminal half-life or volume of distribution do not appear dependent upon the dose.
Regadenoson is moderately bound to human plasma proteins (25-30%).
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. 14
Following intravenous administration of C-radiolabeled regadenoson to rats and dogs, most radioactivity (85-96%) was excreted in the form of unchanged regadenoson. These findings indicate that metabolism of regadenoson does not play a major role in the elimination of regadenoson.
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.
Up to three consecutive injections of regadenoson (100 and 200 μg) have been tested in healthy volunteers, and two consecutive doses of 400 μg in healthy volunteers, as well as in patients assessed for FFR. Transient dose dependent increases in heart rate occurred following administration of each dose of regadenoson, whereas no consistent dose-related effect on systolic blood pressure was observed. Mean plasma concentrations increased in a dose-related manner and by successive doses as observed in healthy volunteers.
A population pharmacokinetic analysis including data from subjects and patients demonstrated that regadenoson clearance decreases in parallel with a reduction in creatinine clearance (CLcr) and increases with increased body weight. Age, gender, and race have minimal effects on the pharmacokinetics of regadenoson.
The disposition of regadenoson was studied in 18 subjects 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 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.
The pharmacokinetics of regadenoson in patients on dialysis has not been assessed.
Greater than 55% of the regadenoson dose is excreted unchanged in the urine and factors that decrease clearance do not affect the plasma concentration in the early stages after dosing when clinically meaningful pharmacologic effects are observed. The pharmacokinetic parameters of regadenoson have not been specifically evaluated in those with varying degrees of hepatic impairment. However, post-hoc analysis of data from the two Phase 3 clinical trials showed that the pharmacokinetics of regadenoson were not affected in a small subset of patients with laboratory values suggestive of impaired hepatic function (2.5-fold transaminase elevation or 1.5-fold elevation of serum bilirubin or prothrombin time). No dose adjustment is needed in patients with hepatic impairment.
Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of regadenoson. No dose adjustment is needed in elderly patients.
The pharmacokinetic parameters of regadenoson have not yet been studied in the paediatric population (<18 years).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, or embryo-fetal development. Signs of maternal and fetal toxicity were seen in rats and rabbits (reduced fetal weights, delays in ossification [rats], reduced litter size and number of live fetuses [rabbits]), but not teratogenicity. Fetal toxicity was noted following repeated daily administration of regadenoson, but at doses sufficiently in excess of the recommended human dose. Fertility and pre- and post-natal studies have not been conducted.
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