RAPISCAN 400 MICROGRAMSSOLUTION FOR INJECTION - summary of medicine characteristics

Rapiscan 400 microgram solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml vial contains 400 micrograms regadenoson (80 micrograms/ml).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection

Clear, colourless solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

This medicinal product is for diagnostic use only.

Rapiscan is a selective coronary vasodilator for use in adults as a pharmacological stress agent for:

myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress.

the measurement of fractional flow reserve (FFR) of a single coronary artery stenosis during invasive coronary angiography, when repeated FFR measurements are not anticipated (see sections 4.2 and 5.1).

4.2 Posology and method of administration

Treatment with Rapiscan is restricted to use in a medical facility where cardiac monitoring and resuscitation equipment are available.

Posology

The recommended dose is a single injection of 400 micrograms regadenoson (5 ml) into a peripheral vein, with no dose adjustment necessary for body weight.

Patients should avoid consumption of any products containing methylxanthines (e.g. caffeine) as well as any medicinal products containing theophylline for at least 12 hours before Rapiscan administration (see section 4.5).

When possible, dipyridamole should be withheld for at least two days prior to Rapiscan administration (see section 4.5).

Aminophylline may be used to attenuate severe and/or persistent adverse reactions to regadenoson but should not be used solely for the purpose of terminating a seizure induced by Rapiscan (see section 4.4).

Regadenoson causes a rapid increase in heart rate (see sections 4.4 and 5.1). Patients should remain sitting or lying down and be monitored at frequent intervals after the injection until the ECG parameters, heart rate and blood pressure have returned to predose levels.

Repeated use

For use in MPI: This product is to be administered only once within a 24-hour period. Safety and tolerability of repeated use of this product within 24 hours has not been characterised.

For use in FFR: This product is to be administered no more than twice, no less than10 minutes apart, during any 24-hour period. When administered twice 10 minutes apart in a 24-hour period, full safety data for the second injection of Rapiscan are not available.

Paediatric population

The safety and efficacy of regadenoson in children below the age of 18 years have not yet been established.

No data are available.

Elderly

No dose adjustment is necessary (see section 5.2).

Hepatic impairment

No dose adjustment is necessary (see section 5.2).

Renal impairment

No dose adjustment is necessary (see section 5.2).

Method of administration

For intravenous use.

Myocardial perfusion imaging (MPI):

Rapiscan should be administered as a rapid, 10-second injection into a peripheral vein using a 22-gauge or larger catheter or needle.

5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection should be

administered immediately after the injection of Rapiscan.

The MPI acquisition protocol should be in line with clinical practice guidelines.

Fractional flow reserve (FFR):

Rapiscan should be administered as a rapid 10-second injection into a peripheral vein, using a 22-gauge or larger catheter or needle

10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection should

be administered immediately after the injection of Rapiscan.

FFR should be measured as the lowest value of Pd/Pa achieved during steady state hyperemia.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Second or third degree atrioventricular (AV) block or sinus node dysfunction, unless these patients have a functioning artificial pacemaker.

Unstable angina that has not been stabilised with medical therapy.

Severe hypotension.

Decompensated states of heart failure.

4.4 Special warnings and precautions for use

Regadenoson has the potential to cause serious and life-threatening reactions, including those listed below (see also section 4.8). Continuous ECG monitoring should be performed and vital signs should be monitored at frequent intervals until the ECG parameters, heart rate and blood pressure have returned to pre-dose levels. Regadenoson should be used with caution and should only be administered in a medical facility with cardiac monitoring and resuscitation equipment. Aminophylline may be administered in doses ranging from 50 mg to 250 mg by slow intravenous injection (50 mg to 100 mg over 30–60 seconds) to attenuate severe and/or persistent adverse reactions to regadenoson but should not be used solely for the purpose of terminating a seizure induced by regadenoson.

Myocardial ischaemia

Fatal cardiac arrest, life-threatening ventricular arrhythmias, and myocardial infarction may result from the ischaemia induced by pharmacologic stress agents like regadenoson.

Regadenoson should be used with caution in patients with recent myocardial infarction.

Single Photon Emission Computed Tomography (SPECT) MPI clinical trials conducted with regadenoson excluded patients with recent (within 3 months) myocardial infarction.

Clinical trials for the measurement of FFR excluded patients with an acute myocardial infarction, or within 5 days of an acute myocardial infarction.

Sinoatrial and atrioventricular nodal block

Adenosine receptor agonists including regadenoson can depress the sinoatrial (SA) and AV nodes and may cause first, second or third degree AV block, or sinus bradycardia.

Hypotension

Adenosine receptor agonists including regadenoson induce arterial vasodilation and hypotension. 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.

Elevated blood pressure

Regadenoson may cause clinically significant increases in blood pressure, which in some patients can lead to hypertensive crisis (see section 4.8). The risk of significant increases in blood pressure may be higher in patients with uncontrolled hypertension. Consideration should be given to delaying regadenoson administration until blood pressure is well controlled

Combination with exercise

Use of regadenoson involving exercise has been associated with serious adverse reactions including hypotension, hypertension, syncope and cardiac arrest. Patients who have had any symptoms or signs suggestive of acute myocardial ischaemia during exercise or recovery are likely to be at especially high risk of serious adverse reactions.

Transient ischaemic attacks and cerebrovascular accident

Regadenoson can cause transient ischaemic attack (see section 4.8). In postmarketing experience there have also been reports of cerebrovascular accident (CVA).

Risk of seizure

Caution should be used when administering regadenoson to patients with a history of seizures or other risk factors for seizures, including the concomitant administration of medicinal products that lower seizure threshold (e.g. antipsychotics, antidepressants, theophyllines, tramadol, systemic steroids and quinolones).

Aminophylline should be used with caution in patients with a history of seizures or who have other risk factors for seizures as it may prolong a seizure or cause multiple seizures because of its proconvulsant effect. Therefore administration of aminophylline solely for the purpose of terminating a seizure induced by regadenoson is not recommended.

Atrial fibrillation or flutter

Regadenoson should be used with caution in patients with a history of atrial fibrillation or flutter. In post- marketing experience there have been cases of worsening or recurrence of atrial fibrillation after administration of regadenoson.

Bronchoconstriction

Regadenoson may cause bronchoconstriction and respiratory arrest (see section 4.8) , especially in patients with known or suspected bronchoconstrictive disease, chronic obstructive pulmonary disease (COPD) or asthma. Appropriate bronchodilator therapy and resuscitative measures should be available prior to regadenoson administration.

Long QT syndrome

Regadenoson stimulates sympathetic output and may increase the risk of ventricular tachyarrhythmias in patients with a long QT syndrome.

Warnings related to excipients

This medicinal product contains less than1 mmol sodium (23 mg) per dose. However, the injection of sodium chloride 9 mg/ml (0.9%) solution given after regadenoson contains 45 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Methylxanthines

Methylxanthines (e.g., caffeine and theophylline) are non-specific adenosine receptor antagonists and may interfere with the vasodilation activity of regadenoson (see section 5.1). Patients should avoid consumption of any medicinal products containing methylxanthines as well as any medicinal products containing theophylline for at least 12 hours before regadenoson administration (see section 4.2).

Dipyridamole

Dipyridamole increases blood adenosine levels and the response to regadenoson may be altered when blood adenosine levels are increased. When possible, dipyridamole should be withheld for at least two days prior to regadenoson administration (see section 4.2).

Cardioactive medicinal products

In clinical studies, regadenoson was administered to patients taking other cardioactive medicinal products (i.e., P-blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, and angiotensin receptor blockers) without apparent effects on the safety or efficacy profile of regadenoson.

Other interactions

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 medicinal products metabolised by these cytochrome P450 enzymes.

Regadenoson does not significantly inhibit the transporters OAT1, OAT3, OCT1, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, BSEP, ENT 1 or ENT2 at 1 |jM. The data are insufficient to conclude about the risk of interactions at the level of these transporters given that a single concentration was evaluated in most instances.

Regadenoson may have a modest inhibitory effect on the active renal transporter, OCT2, and has been found to be likely substrate for BCRP, ENT1 or ENT2 mediated transport. However, given the proposed duration of use, the effects of the drug transporters are unlikely to be clinically relevant.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of regadenoson in pregnant women. Animal studies on pre- and post-natal development have not been conducted. Fetotoxicity, but not teratogenicity, was noted in embryo-fetal development studies (see section 5.3). The potential risk for humans is unknown. Regadenoson should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is unknown whether regadenoson is excreted in human breast milk. The excretion of regadenoson in milk has not been studied in animals. A decision should be made whether to discontinue breast- feeding or to abstain from regadenoson administration taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. If regadenoson is administered, the woman should not breastfeed for at least 10 hours (that is, at least 5 times the plasma elimination half-life) following regadenoson administration.

Fertility

Fertility studies with regadenoson have not been performed (see section 5.3).

4.7 Effects on ability to drive and use machines

Regadenoson administration may result in adverse reactions such as dizziness, headache, and dyspnoea (see section 4.8) soon after administration. However, most adverse reactions are mild and transient, resolving within 30 minutes after receiving regadenoson. Therefore, regadenoson would be expected to have no or negligible influence on the ability to drive or use machines once treatment has been completed and these reactions have resolved.

4.8 Undesirable effects

Summary of the safety profile

Adverse reactions in most patients receiving regadenoson in clinical trials were mild, transient (usually resolving within 30 minutes after receiving regadenoson) and required no medical intervention. Adverse reactions occurred in approximately 80% of patients. The most common adverse reactions reported during clinical development in a total of 1,651 patients/sub­jects were: dyspnoea (29%), headache (27%), flushing (23%), chest pain (19%), electrocardiogram ST segment changes (18%), gastrointestinal discomfort (15%) and dizziness (11%).

Regadenoson may cause myocardial ischaemia (potentially associated with fatal cardiac arrest, life- threatening ventricular arrhythmias, and myocardial infarction), hypotension leading to syncope and transient ischaemic attacks, elevated blood pressure leading to hypertension and hypertensive crises,_and SA/AV node block leading to first, second or third degree AV block, or sinus bradycardia requiring intervention (see section 4.4). Signs of hypersensitivity (rash, urticaria, angioedema, anaphylaxis and/or throat tightness) may be immediate or delayed onset. Aminophylline may be used to attenuate severe or persistent adverse reactions to regadenoson but should not be used solely for the purpose of terminating a seizure induced by regadenoson (see section 4.4).

Tabulated list of adverse reactions

Assessment of adverse reactions for regadenoson is based on safety data from clinical studies and post-marketing experience. All adverse reactions are presented in the table below and are listed by system organ class and frequency. Frequencies are defined as very common (> 1/10), common

(> 1/100 to < 1/10) uncommon (> 1/1,000 to < 1/100) and rare (> 1/10,000 to < 1/1,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Fatal cardiac arrest, life-threatening ventricular arrhythmias and myocardial infarction may result from the ischaemia induced by pharmacologic stress agents. Cardiac resuscitation equipment and trained staff should be available before administering regadenoson (see section 4.4).

Sinoatrial and atrioventricular nodal block

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 postmarketing experience, third degree heart block and asystole have been reported within minutes of regadenoson administration.

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 postmarketing experience, syncope and transient ischaemic attacks have been reported.

Elevated blood pressure

In clinical trials, increased systolic blood pressure (> 50 mm Hg) was observed in 0.7% of patients and increased diastolic blood pressure (> 30 mm Hg) in 0.5% of patients. Most increases resolved within 10 to 15 minutes, but in some cases, increases were observed at 45 minutes following administration.

Long QT syndrome

Regadenoson increases sympathetic tone, which causes an increase in heart rate and a shortening of the QT interval. In a patient with a long QT syndrome, sympathetic stimulation can result in less shortening of the QT interval than is normal and may even cause a paradoxical increase in the QT interval. In these patients, the phenomenon of R-on-T syndrome can occur, wherein an extra beat interrupts the T wave of the previous beat, and this increases the risk of a ventricular tachyarrhythmia.

Headache

Headache was reported by 27% of subjects who received regadenoson in clinical trials. The headache was considered severe in 3% of subjects.

Elderly , population

Older patients (> 75 years of age; n = 321) had a similar adverse reaction profile compared to younger patients (< 65 years of age; n = 1,016), but had a higher incidence of hypotension (2% versus < 1%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at https://yellowcard.mhra.gov.uk/

4.9 Overdose

In a study of healthy volunteers, symptoms of flushing, dizziness and increased heart rate were assessed as intolerable at regadenoson doses greater than 0.02 mg/kg.

Treatment

Aminophylline may be used to attenuate severe or persistent adverse reactions to regadenoson. Administration of aminophylline, solely for the purpose of terminating a regadenoson-induced seizure is not recommended (see section 4.4).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB21

Mechanism of action

Regadenoson is a low affinity agonist (Ki ~ 1.3 pM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 pM), 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.

Pharmacodynamic effects

Coronary blood f flow

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.

Myocardial perfusion imaging (MP I)

Haemodynamic effects

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. However, heart rate increases of up to 42 bpm are reported in the literature (discussed below in the CMR MPI section). 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 mm Hg 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).

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 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.

Fractional Flow Reserve (FFR)

Haemodynamic Effects

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 efficacy and safety

Clinical studies have demonstrated the efficacy and safety of regadenoson in patients indicated for pharmacologic stress Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), Cardiac Magnetic Resonance (CMR) and MultiDetector Computed Tomography (MDCT) MPI and for the measurement of FFR.

Regadenoson-stress SPECT MPI

The efficacy and safety of regadenoson for regadenoson-stress SPECT 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 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 SPECT 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 P—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:

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.

Regadenoson-stress PET MPI

Intraindividual comparison of regadenoson (0.4 mg/ 5 ml bolus) versus dipyridamole (0.57 mg/kg for 4 minutes) was performed in a prospective study recruiting 32 subjects (23 males and 9 females, mean age of 62 ± 12.1). From those, 26 had a reversible perfusion defect already identified on a previous clinically indicated dipyridamole-stress PET study with 82RbCl and 6 subjects with <5% pre-test likelihood for CAD showed no defects on dipyridamole PET images. The study included patients with a mild-moderate degree of ischemia with a small proportion of patients having moderate to severe ischemia, and they had normal or near-normal left ventricular function.

In this study the 82RbCl infusion started promptly after regadenoson injection (that is, imaging started 2 minutes following start of 82Rb infusion). Visual interpretation of PET images indicated no difference in the number of segments with reversible defects between regadenoson and dipyridamole for 30/32 image pairs.

Results may not be generalizable to patients with slowed circulation times associated with left or right heart failure, pulmonary hypertension, or morbid obesity, who may have a delay in transit of the tracer arriving after the peak phase.

Regadenoson-stress CMR MPI

Intraindividual comparison of regadenoson- versus adenosine-stress CMR MPI was performed in a prospective study in relation to the caused coronary hyperemia across the range of body sizes seen in a clinical setting. Twentyeight subjects (12 female, 16 males) were imaged: 43% were obese and 25% had one or more known coronary risk factors. MR imaging with Gd-BOPTA was done first at rest, then during adenosine infusion (140 gg/ kg/min) and 30 min later with regadenoson (0.4 mg over 10 s/ 5 ml bolus). The study showed both vasodilators having a similar efficacy on vasodilation (good agreement between myocardial perfusion reserve (MPR) measured with adenosine and regadenoson (y = 1.1× – 0.06, r = 0.7)). The studied population would likely not include the broad spectrum of body sizes as might be seen in patients in daily CMR MPI.

Intraindividual comparison of regadenoson versus adenosine was performed in a prospective study to evaluate the effects of vasodilators on CMR-derived ventricular volumes and function in 25 healthy subjects. CMR was performed following adenosine (140 pg/kg/min IV for 6 min) and regadenoson (0.4 mg IV over 10 s) at baseline, immediately following administration, then at 5 min intervals up to 15 min. Peak heart rate was observed early following administration of both adenosine and regadenoson. The increase from baseline to peak heart rate immediately following vasodilator administration was 64 ± 8 to 96 ± 13 bpm for adenosine vs 65 ± 13 to 107 ± 10 bpm for regadenoson. Heart rate returned to baseline by 10 min post-adenosine while remaining elevated at 15 min post-regadenoson. Left ventricular ejection fraction (LVEF) increased immediately following both vasodilators and returned to baseline following adenosine by 10 min, but remained increased at 15 min following regadenoson. Regadenoson resulted in a similar magnitude reduction in both LV end-diastolic volume index (LVEDVi) and LV end-systolic volume index (LVESVi) at 15 min whereas LVESVi resolved at 15 min following adenosine and LVEDVi remained below baseline values.

Intraindividual comparison was conducted in a prospective study to determine the relative potency of regadenoson (400 pg in bolus), adenosine (140 pg/kg/min over 5 to 6 minutes), and dipyridamole (0.56 mg/kg over 4 minutes) by quantifying stress and rest myocardial perfusion using CMR in 50 young healthy male volunteers. The protocol used in this study as rest-stress imaging is different from currently used protocols: initial rest perfusion CMR imaging, followed twenty minutes later by stress imaging performed at peak vasodilation. Regadenoson produced higher stress myocardial blood flow (MBF) than dipyridamole and adenosine (3.58±0.58 vs. 2.81±0.67 vs.

2.78±0.61 ml/min/g, p=0.0009 and p=0.0008 respec­tively). Regadenoson had a higher heart rate response than adenosine and dipyridamole (95±11 vs.76±13 vs. 86±12 beats/minute respectively).

When stress MBF was adjusted for heart rate, there were no differences between regadenoson and adenosine (37.8±6 vs. 36.6±4pl/sec/g,), but differences between regadenoson and dipyridamole persisted (37.8 ± 6 vs. 32.6 ± 5pl/sec/g, p=0.03).

Regadenonon-stress MDCT MPI

A Phase 2, multicenter, open-label, randomized, cross-over prospective study was sponsored (Study 3606-CL-2001) to determine agreement rate between regadenoson stress SPECT and regadenoson-stress CT perfusion for detecting the presence of ischemia (defined as 2 or more reversible defects seen visually) in 110 patients with suspected or known CAD referred for one of these diagnostic tests as being clinically indicated. Subjects were randomized to 1 of 2 imaging procedure sequences and to undergo both a rest/stress SPECT and a rest/stress MDCT. Regadenoson was administered as 0.4 mg in a 5 mL IV bolus prior to each stress CT perfusion and stress SPECT procedure.

While regadenoson stress SPECT imaging identified 100 subjects as having 0 – 1 reversible defects (i.e. no ischemia) and 10 subjects as having > 2 reversible defects (i.e. ischemia), regadenoson stress MDCT imaging identified 85 and 25 subjects as having 0 –1 or > 2 reversible defects, respectively. The agreement rate between regadenoson stress SPECT and regadenoson stress MDCT MPI was 87% (95% CI: 77%, 97%).

Suboptimal Exercise Stress Test

In the EXERRT trial the efficacy and safety of regadenoson was evaluated in patients with suboptimal Exercise Stress in an open-label randomized, multicenter, 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 SPECT 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.

Measurement ofFFR

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 ng). 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.

Aminophylline

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).

Effect of caffeine

In a study of adult patients undergoing pharmacological stress SPECT 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.

Safety and tolerability testing

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.

Paediatric population

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).

5.2 Pharmacokinetic properties

Absorption

Regadenoson is administered by intravenous injection for pharmacologic stress MPI. The regadenoson plasma concentration-time profile in healthy volunteers is multiexponential 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.

Distribution

Regadenoson is moderately bound to human plasma proteins (25–30%).

Biotransformation

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. 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.

Elimination

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.

Multiple injections

Up to three consecutive injections of regadenoson (100 and 200 pg) have been tested in healthy volunteers, and two consecutive doses of 400 pg 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. Special populations

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.

Renal impairment

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 > 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.

The pharmacokinetics of regadenoson in patients on dialysis has not been assessed.

Hepatic impairment

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.

Elderly 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.

Paediatric population

The pharmacokinetic parameters of regadenoson have not yet been studied in the paediatric population (< 18 years).

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium phosphate dihydrate

Sodium dihydrogen phosphate monohydrate

Propylene glycol

Disodium edetate

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

5 ml solution in a single use Type 1 glass vial with (butyl) rubber stopper and aluminium over-seal.

Pack size of 1.

6.6 Special precautions for disposal

This medicinal product should be inspected visually for particulate matter and discolouration prior to administration.

Any unused product or waste material should be disposed of in accordance with local requirements.

GE Healthcare Limited

Pollards Wood Nightingales Lane Chalfont St Giles Buckinghamshire HP8 4SP United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 00221/0395

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/01/2021