RAPISCAN 400mcg 80mcg / ml solution for injection medication leaflet

Rapiscan 400 microgram solution for injection

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

For the full list of excipients, see section 6.1.

Solution for injection

Clear, colourless solution.

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 duringinvasive coronary angiography, when repeated FFR measurements are not anticipated (seesections 4.2 and 5.1).

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

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

Patients should avoid consumption of any products containing methylxanthines (e.g. caffeine) as wellas 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 butshould not be used solely for the purpose of terminating a seizure induced by Rapiscan (see section4.4).

Regadenoson causes a rapid increase in heart rate (see sections 4.4 and 5.1). Patients should remainsitting or lying down and be monitored at frequent intervals after the injection until the ECGparameters, heart rate and blood pressure have returned to pre-dose levels.

Repeated use

For use in MPI: This product is to be administered only once within a 24 hour period. Safety andtolerability 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 safetydata for the second injection of Rapiscan are not available.

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

No data are available.

No dose adjustment is necessary (see section 5.2).

No dose adjustment is necessary (see section 5.2).

No dose adjustment is necessary (see section 5.2).

For intravenous use.

Myocardial perfusion imaging (MPI):

* Rapiscan should be administered as a rapid, 10-second injection into a peripheral vein using a22-gauge or larger catheter or needle.

* 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection should be administeredimmediately 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 a22-gauge or larger catheter or needle

* 10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection should be administeredimmediately after the injection of Rapiscan.

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

* 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 patientshave a functioning artificial pacemaker.

* Unstable angina that has not been stabilised with medical therapy.

* Severe hypotension.

* Decompensated states of heart failure.

Regadenoson has the potential to cause serious and life-threatening reactions, including those listedbelow (see also section 4.8). Continuous ECG monitoring should be performed and vital signs shouldbe monitored at frequent intervals until the ECG parameters, heart rate and blood pressure havereturned to pre-dose levels. Regadenoson should be used with caution and should only be administeredin a medical facility with cardiac monitoring and resuscitation equipment. Aminophylline may beadministered in doses ranging from 50 mg to 250 mg by slow intravenous injection (50 mg to 100 mgover 30-60 seconds) to attenuate severe and/or persistent adverse reactions to regadenoson but shouldnot 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 resultfrom 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 withregadenoson excluded patients with recent (within 3 months) myocardial infarction.

Clinical trials for the measurement of FFR excluded patients with an acute myocardial infarction, orwithin 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 andmay cause first, second or third degree AV block, or sinus bradycardia.

Adenosine receptor agonists including regadenoson induce arterial vasodilation and hypotension. Therisk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, leftmain coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, orstenotic carotid artery disease with cerebrovascular insufficiency.

Elevated blood pressure

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

Combination with exercise

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

Transient ischaemic attacks and cerebrovascular accident

Regadenoson can cause transient ischaemic attack (see section 4.8). In post-marketing experiencethere have also been reports of cerebrovascular accident (CVA).

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

Aminophylline should be used with caution in patients with a history of seizures or who have otherrisk factors for seizures as it may prolong a seizure or cause multiple seizures because of itsproconvulsant effect. Therefore administration of aminophylline solely for the purpose of terminatinga 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. Inpost- marketing experience there have been cases of worsening or recurrence of atrial fibrillation afteradministration of regadenoson.

Bronchoconstriction

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

Long QT syndrome

Regadenoson stimulates sympathetic output and may increase the risk of ventricular tachyarrhythmiasin 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 ofsodium chloride 9 mg/ml (0.9%) solution given after regadenoson contains 45 mg of sodium. To betaken into consideration by patients on a controlled sodium diet.

Methylxanthines

Methylxanthines (e.g., caffeine and theophylline) are non-specific adenosine receptor antagonists andmay interfere with the vasodilation activity of regadenoson (see section 5.1). Patients should avoidconsumption of any medicinal products containing methylxanthines as well as any medicinal productscontaining 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 whenblood adenosine levels are increased. When possible, dipyridamole should be withheld for at least twodays prior to regadenoson administration (see section 4.2).

Cardioactive medicinal products

In clinical studies, regadenoson was administered to patients taking other cardioactive medicinalproducts (i.e., β-blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, andangiotensin receptor blockers) without apparent effects on the safety or efficacy profile ofregadenoson.

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 thepharmacokinetics 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 µM. The data areinsufficient to conclude about the risk of interactions at the level of these transporters given that asingle concentration was evaluated in most instances.

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

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 inembryo-fetal development studies (see section 5.3). The potential risk for humans is unknown.

Regadenoson should not be used during pregnancy unless clearly necessary.

It is unknown whether regadenoson is excreted in human breast milk. The excretion of regadenoson inmilk 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-feedingfor the child and the benefit of therapy for the woman. If regadenoson is administered, the womanshould not breast-feed for at least 10 hours (that is, at least 5 times the plasma elimination half-life)following regadenoson administration.

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

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

Adverse reactions in most patients receiving regadenoson in clinical trials were mild, transient (usuallyresolving within 30 minutes after receiving regadenoson) and required no medical intervention.

Adverse reactions occurred in approximately 80% of patients. The most common adverse reactionsreported 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 andtransient 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 bradycardiarequiring 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 usedto attenuate severe or persistent adverse reactions to regadenoson but should not be used solely for thepurpose of terminating a seizure induced by regadenoson (see section 4.4).

Assessment of adverse reactions for regadenoson is based on safety data from clinical studies andpost-marketing experience. All adverse reactions are presented in the table below and are listed bysystem 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 eachfrequency grouping, adverse reactions are presented in order of decreasing seriousness.

Uncommon Hypersensitivity reactions including: Rash, urticaria, angioedema, anaphylaxisand/or throat tightness.

Uncommon Anxiety, insomnia

Very common Headache, dizziness

Common Paraesthesia, hypoaesthesia, dysgeusia

Uncommon Convulsions, syncope, transient ischaemic attack, unresponsiveness to stimuli,depressed level of consciousness, tremor, somnolence

Rare Cerebrovascular accident

Uncommon Vision blurred, eye pain

Ear and labyrinth disorders:

Uncommon Tinnitus

Very common Electrocardiogram ST segment changes

Common Angina pectoris, atrioventricular block, tachycardia, palpitations, other

ECG abnormalities including electrocardiogram QT corrected interval prolonged

Uncommon Cardiac arrest, myocardial infarction, complete AV block, bradycardia, atrial flutter,new-onset, worsening or recurrence of atrial fibrillation

Very common Flushing

Common Hypotension

Uncommon Hypertension, pallor, peripheral coldness

Very common Dyspnoea

Common Throat tightness, throat irritation, cough

Uncommon Tachypnoea, wheezing

Not known Bronchospasm, Respiratory arrest

Very common Gastrointestinal discomfort

Common Vomiting, nausea, oral discomfort

Uncommon Abdominal distension, diarrhoea, faecal incontinence

Common Hyperhidrosis

Uncommon Erythema

Common Back, neck or jaw pain, pain in extremity, musculoskeletal discomfort

Uncommon Arthralgia

Very common Chest pain

Common Malaise, asthenia

Uncommon Pain at injection site, general body pain

Fatal cardiac arrest, life-threatening ventricular arrhythmias and myocardial infarction may result fromthe ischaemia induced by pharmacologic stress agents. Cardiac resuscitation equipment and trainedstaff 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 AVblock, or sinus bradycardia requiring intervention. In clinical trials first degree AV block (PRprolongation > 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 receivingregadenoson. In postmarketing experience, third degree heart block and asystole have been reportedwithin minutes of regadenoson administration.

Adenosine receptor agonists, including regadenoson induce arterial vasodilation and hypotension. Inclinical trials, decreased systolic blood pressure (> 35 mm Hg) was observed in 7% of patients anddecreased diastolic blood pressure (> 25 mm Hg) was observed in 4% of patients within 45 minutes ofregadenoson administration. The risk of serious hypotension may be higher in patients with autonomicdysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease,pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascularinsufficiency. In postmarketing experience, syncope and transient ischaemic attacks have beenreported.

Elevated blood pressure

In clinical trials, increased systolic blood pressure (≥ 50 mm Hg) was observed in 0.7% of patients andincreased diastolic blood pressure (≥ 30 mm Hg) in 0.5% of patients. Most increases resolved within10 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 ofthe QT interval. In a patient with a long QT syndrome, sympathetic stimulation can result in lessshortening of the QT interval than is normal and may even cause a paradoxical increase in the QTinterval. In these patients, the phenomenon of R-on-T syndrome can occur, wherein an extra beatinterrupts the T wave of the previous beat, and this increases the risk of a ventricular tachyarrhythmia.

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

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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 seizureis not recommended (see section 4.4).

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 coronaryvasodilation and increases coronary blood flow (CBF). Despite low affinity for the A2A adenosinereceptor, regadenoson has high potency for increasing coronary conductance in rat and guinea pigisolated hearts, with EC50 values of 6.4 nM and 6.7-18.6 nM, respectively. Regadenoson showsselectivity (≥ 215-fold) for increasing coronary conductance (A2A-mediated response) relative toslowing 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 incoronary relative to peripheral (forelimb, brain, pulmonary) arterial vascular beds in the anaesthetiseddog.

Coronary blood flow

Regadenoson causes a rapid increase in CBF which is sustained for a short duration. In patientsundergoing coronary catheterisation, pulsed-wave Doppler ultrasonography was used to measure theaverage 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 secondsand 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 increasesblood flow in normal coronary arteries with little or no increase in stenotic arteries, regadenosoncauses relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenoticarteries. Myocardial radiopharmaceutical uptake after regadenoson administration is therefore greaterin areas perfused by normal relative to stenosed arteries. The same applies to the FFR measurementwhere the maximal myocardial blood flow is decreased in presence of severe coronary artery stenosis.

Myocardial perfusion imaging (MPI)

Haemodynamic effects

The majority of patients experience a rapid increase in heart rate. The greatest mean change frombaseline (21 bpm) occurs approximately 1 minute after administration of regadenoson. However, heartrate increases of up to 42 bpm are reported in the literature (discussed below in the CMR MPIsection). Heart rate returns to baseline within 10 minutes. Systolic blood pressure and diastolic bloodpressure changes were variable, with the greatest mean change in systolic pressure of −3 mm Hg andin diastolic pressure of −4 mm Hg approximately 1 minute after regadenoson administration. Anincrease in blood pressure has been observed in some patients (maximum systolic blood pressure of240 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 ofbronchoconstriction in susceptible individuals (i.e., asthmatics). In in vitro studies, regadenoson hasbeen 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 threerandomised, 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 andplacebo dosing, respectively (p=0.31). In the second study in 48 patients with mild to moderate asthmawho 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 andplacebo dosing. In the third study in 1009 patients with mild or moderate asthma (n=537) andmoderate 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, dyspnoeawas 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. Inthe 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 clinicaldevelopment (see Section 4.8). A relationship between increased severity of disease and the increasedincidence of dyspnoea was apparent in patients with asthma, but not in patients with COPD. The useof 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 meanduration of hyperaemic plateau was 163 (±169) seconds and maximum hyperaemia lasted at least19 seconds in 90% of patients, however, in the individual patient the duration of hyperaemia variedbetween 10 seconds to more than 10 minutes. Hyperaemia may fluctuate between sub-maximum andmaximum until it slowly vanishes. The 10-second window of steady state hyperaemia can be too shortfor performing extensive pressure pullback recordings to assess complex or diffuse coronary arterydisease. Repeat dosing within 10 minutes - except in patients where the duration of hyperaemia lastedfor 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 forpharmacologic 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 relativeto adenosine in two randomised, double-blind studies (ADVANCE MPI 1 and ADVANCE MPI 2) in2,015 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 forthe primary efficacy evaluation, including 1,294 (69%) men and 577 (31%) women with a median ageof 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 (singlephoton emission computed tomography) imaging protocol. After the initial scan, patients wererandomised 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 of1-104 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 includeddiabetes (32%) and COPD (5%). Patients with a recent history of serious uncontrolled ventriculararrhythmia, 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 numberof 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 wasperformed as follows. Using the 17-segment model, the number of segments showing a reversibleperfusion defect was calculated for the initial adenosine study and for the randomised study obtainedusing regadenoson or adenosine. In the pooled study population, 68% of patients had 0-1 segmentsshowing reversible defects on the initial scan, 24% had 2-4 segments, and 9% had ≥ 5 segments. Theagreement rate for the image obtained with regadenoson or adenosine relative to the initial adenosineimage was calculated by determining how frequently the patients assigned to each initial adenosinecategory (0-1, 2-4, 5-17 reversible segments) were placed in the same category with the randomisedscan. The agreement rates for regadenoson and adenosine were calculated as the average of theagreement 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 toadenosine in assessing the extent of reversible perfusion abnormalities:

ADVANCE ADVANCE Combined

MPI 1 MPI 2 Studies(n = 1,113) (n = 758) (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 weightedkappas of the median score of three blinded readers with respect to ischaemia size category (notcounting segments with normal rest uptake and mild/equivocal reduction in stress uptake asischaemic) for the combined studies of regadenoson with the adenosine scan were moderate, 0.53 and0.61, 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 for4 minutes) was performed in a prospective study recruiting 32 subjects (23 males and 9 females, meanage of 62 ± 12.1). From those,26 had a reversible perfusion defect already identified on a previousclinically indicated dipyridamole-stress PET study with 82RbCl and 6 subjects with <5% pre-testlikelihood for CAD showed no defects on dipyridamole PET images. The study included patients witha mild-moderate degree of ischemia with a small proportion of patients having moderate to severeischemia, and they had normal or near-normal left ventricular function.

In this study the 82RbCl infusion started promptly after regadenoson injection (that is, imaging started2 minutes following start of 82Rb infusion). Visual interpretation of PET images indicated nodifference in the number of segments with reversible defects between regadenoson and dipyridamolefor 30/32 image pairs.

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

Regadenoson-stress CMR MPI

Intraindividual comparison of regadenoson- versus adenosine-stress CMR MPI was performed in aprospective study in relation to the caused coronary hyperemia across the range of body sizes seen in aclinical setting. Twenty-eight 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 µg/ 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 (goodagreement between myocardial perfusion reserve (MPR) measured with adenosine and regadenoson (y= 1.1x - 0.06, r = 0.7)). The studied population would likely not include the broad spectrum of bodysizes as might be seen in patients in daily CMR MPI.

Intraindividual comparison of regadenoson versus adenosine was performed in a prospective study toevaluate the effects of vasodilators on CMR-derived ventricular volumes and function in 25 healthysubjects. CMR was performed following adenosine (140 µg/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 to15 min. Peak heart rate was observed early following administration of both adenosine andregadenoson. The increase from baseline to peak heart rate immediately following vasodilatoradministration 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 bothvasodilators and returned to baseline following adenosine by 10 min, but remained increased at 15 minfollowing 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 ofregadenoson (400 μg in bolus), adenosine (140 μg/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 15young healthy normal volunteers. The protocol used in this study as rest-stress imaging is differentfrom currently used protocols: initial rest perfusion CMR imaging, followed twenty minutes later bystress imaging performed at peak vasodilation. Regadenoson produced higher stress myocardial bloodflow (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 adenosineand dipyridamole (95±11 vs.76±13 vs. 86±12 beats/minute respectively). When stress MBF wasadjusted for heart rate, there were no differences between regadenoson and adenosine(37.8±6vs.36.6±4μl/sec/g,), but differences between regadenoson and dipyridamole persisted(37.8±6vs.32.6±5μl/sec/g, p=0.03).

Regadenonon-stress MDCT MPI

A Phase 2, multicenter, open-label, randomized, cross-over prospective study was sponsored (Study3606-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 defectsseen visually) in 110 patients with suspected or known CAD referred for one of these diagnostic testsas being clinically indicated. Subjects were randomized to 1 of 2 imaging procedure sequences and toundergo both a rest/stress SPECT and a rest/stress MDCT. Regadenoson was administered as 0.4 mgin 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, multi-center, non-inferiority study when regadenosonadministered 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 2009guidelines.

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), transitionedinto a 3-5 minutes walking recovery where during the first 3 minutes of recovery, patients wererandomized 1:1.

Therefore, 1147 patients were randomized in two groups: 578 patients from the exercise withregadenoson group and 569 from the regadenoson only group to either 3 minutes recovery (for theexercise 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 regadenosononly groups constituted the MPI 1 phase.

Subsequentially, patients from both groups, returned 1-14 days later, to undergo a second stress MPIregadenoson 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 wassimilar 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 wasreported. Upon case review, both patients, experienced ischemic symptoms and ECG changes duringexercise or recovery prior to regadenoson administration.

No serious cardiac adverse reactions occurred in patients receiving regadenoson 1 hour followinginadequate exercise stress.

Measurement of FFR

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 unpredictablyand 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 ofinducible ischemia). Adenosine was treated as a gold standard to estimate sensitivity, specificity, andthe proportion of accuracy.

Study Sensitivity Specificity Classification agreement

Cohen’s kappa

Stolker et al. 2015 (n=149) 98% 97% 0.94van Nunen et al. 2015 (n=98) 98% 95% 0.94

Aminophylline

Aminophylline (100 mg, administered by slow intravenous injection over 60 seconds) injected 1minute after 400 micrograms regadenoson in subjects undergoing cardiac catheterisation, was shownto 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 toregadenoson (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 minutesbefore 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 plasmaconcentrations.

Safety and tolerability testing

In ADVANCE MPI 1 and ADVANCE MPI 2, the following pre-specified safety and tolerabilityendpoints comparing regadenoson to adenosine achieved statistical significance: (1) a summed scoreof both the presence and severity of the symptom groups of flushing, chest pain, and dyspnoea waslower with regadenoson (0.9 ± 0.03) than with adenosine (1.3 ± 0.05); and (2) the symptom groups offlushing (21% vs 32%), chest pain (28% vs 40%), and ‘throat, neck or jaw pain’ (7% vs 13%) wereless frequent with regadenoson ; the incidence of headache (25% vs 16%) was more frequent withregadenoson .

The European Medicines Agency has deferred the obligation to submit the results of studies withregadenoson in one or more subsets of the paediatric population with myocardial perfusiondisturbances (see section 4.2 for information on paediatric use).

Regadenoson is administered by intravenous injection for pharmacologic stress MPI. Theregadenoson plasma concentration-time profile in healthy volunteers is multi-exponential in natureand best characterised by 3-compartment model. The maximal plasma concentration of regadenoson isachieved within 1 to 4 minutes after injection of regadenoson and parallels the onset of thepharmacodynamic response (see section 5.1). The half-life of this initial phase is approximately 2 to 4minutes. An intermediate phase follows, with a half-life on average of 30 minutes coinciding with lossof the pharmacodynamic effect. The terminal phase consists of a decline in plasma concentration witha half-life of approximately 2 hours. Within the dose range of 0.003-0.02 mg/kg (or approximately0.18-1.2 mg) in healthy subjects, clearance, terminal half-life or volume of distribution do not appeardependent 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 livermicrosomes as well as human hepatocytes produced no detectable metabolites of regadenoson.

Following intravenous administration of C-radiolabeled regadenoson to rats and dogs, mostradioactivity (85-96%) was excreted in the form of unchanged regadenoson. These findings indicatethat 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 glomerularfiltration 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 μg) have been tested in healthyvolunteers, and two consecutive doses of 400 μg in healthy volunteers, as well as in patients assessedfor FFR. Transient dose dependent increases in heart rate occurred following administration of eachdose of regadenoson, whereas no consistent dose-related effect on systolic blood pressure wasobserved. Mean plasma concentrations increased in a dose-related manner and by successive doses asobserved in healthy volunteers.

A population pharmacokinetic analysis including data from subjects and patients demonstrated thatregadenoson clearance decreases in parallel with a reduction in creatinine clearance (CLcr) andincreases with increased body weight. Age, gender, and race have minimal effects on thepharmacokinetics of regadenoson.

The disposition of regadenoson was studied in 18 subjects with various degrees of renal function andin 6 healthy subjects. With increasing renal impairment, from mild (CLcr 50 to < 80 ml/min) tomoderate (CLcr 30 to < 50 ml/min) to severe renal impairment (CLcr < 30 ml/min), the fraction ofregadenoson excreted unchanged in urine and the renal clearance decreased, resulting in increasedelimination 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 weresimilar across the groups. The plasma concentration-time profiles were not significantly altered in theearly stages after dosing when most pharmacologic effects are observed. No dose adjustment is neededin 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 decreaseclearance do not affect the plasma concentration in the early stages after dosing when clinicallymeaningful pharmacologic effects are observed. The pharmacokinetic parameters of regadenoson havenot 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 ofregadenoson were not affected in a small subset of patients with laboratory values suggestive ofimpaired hepatic function (2.5-fold transaminase elevation or 1.5-fold elevation of serum bilirubin orprothrombin 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 ofregadenoson. 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 safetypharmacology, single and repeated dose toxicity, genotoxicity, or embryo-fetal development. Signs ofmaternal 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 wasnoted following repeated daily administration of regadenoson, but at doses sufficiently in excess of therecommended human dose. Fertility and pre- and post-natal studies have not been conducted.

Disodium phosphate

Sodium dihydrogen phosphate

Disodium edetate

Water for injections

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

5 ml vial: 4 years7 ml vial: 2.5 years

This medicinal product does not require any special storage conditions.

5 ml solution in a single use 5 ml or 7 ml Type 1 glass vial with (butyl) rubber stopper and aluminiumover-seal.

Pack size of 1.

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

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

GE Healthcare AS

Nycoveien 1

NO-0485 Oslo

Norway

EU/1/10/643/001

Date of first authorisation: 06/09/2010

Date of latest renewal: 24/04/2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.