Each 5 ml vial contains 400 micrograms regadenoson (80 micrograms/ml). Excipient(s): Each 5 ml vial contains 19.26 mg of sodium. For a full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Posology and method of administration

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

The recommended dose of Rapiscan 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 Rapiscan (see section 4.4). Rapiscan 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 pre-dose levels.

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.

The safety and efficacy of Rapiscan in children below the age of 18 years have not yet been established. No data are available.

immediately after the injection of Rapiscan. The radiopharmaceutical for the myocardial perfusion imaging agent should be administered 10-20 seconds after the sodium chloride 9 mg/ml (0.9%) solution for injection. The radiopharmaceutical may be injected directly into the same catheter as Rapiscan.

Contraindications

patients have a functioning artificial pacemaker. Unstable angina that has not been stabilised with medical therapy. Severe hypotension. Decompensated states of heart failure.

Special warnings and precautions for use

Rapiscan 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. Rapiscan 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 Rapiscan.

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

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.

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.

Adenosine receptor agonists may cause bronchoconstriction and respiratory compromise. For 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 Rapiscan administration.

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

This medicinal product contains less than 1 mmol sodium (23 mg) per dose. However, the injection of sodium chloride 9 mg/ml (0.9%) solution given after Rapiscan contains 45 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

Interaction with other medicinal products and other forms of interaction

No studies of interaction with other medicinal products have been performed. 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 products containing methylxanthines as well as any medicinal products containing theophylline for at least 12 hours before Rapiscan administration (see section 4.2). 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 Rapiscan (see section 4.4).

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 Rapiscan administration (see section 4.2).

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

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.

Fertility, pregnancy and lactation

There are no adequate data from the use of Rapiscan 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. Rapiscan should not be used during pregnancy unless clearly necessary.

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 Rapiscan administration taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. If Rapiscan is administered, the woman should not breast-feed for at least 10 hours (that is, at least 5 times the plasma elimination half-life) following Rapiscan administration.

Effects on ability to drive and use machines

No studies on the effects of Rapiscan on the ability to drive and use machines have been performed. Rapiscan 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 Rapiscan. Therefore, Rapiscan would be expected to have no or negligible influence on the ability to drive or operate machinery once treatment has been completed and these reactions have resolved. The physician is advised to provide a recommendation for the individual patient.

Undesirable effects

Summary of the safety profile

Adverse reactions in most patients receiving Rapiscan in clinical trials were mild, transient (usually resolving within 30 minutes after receiving Rapiscan), 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%). Rapiscan 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, 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 Rapiscan (see section 4.4).

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

Immune system disorders:
Uncommon	Hypersensitivity reactions including: Rash, urticaria, angioedema, anaphylaxis
Psychiatric disorders:
Uncommon	Anxiety, insomnia
Nervous system disorders:
Very common	Headache, dizziness
Common	Paraesthesia, hypoaesthesia, dysgeusia
Uncommon	Convulsions, syncope, transient ischaemic attack, unresponsiveness to stimuli, depressed level of consciousness, tremor, somnolence
Eye disorders:
Uncommon	Vision blurred, eye pain
Ear and labyrinth disorders:
Uncommon	Tinnitus
Cardiac disorders:
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, atrial fibrillation/flutter, bradycardia
Vascular disorders:
Very common	Flushing
Common	Hypotension
Uncommon	Hypertension, pallor, peripheral coldness
Respiratory, thoracic and mediastinal disorders:
Very common	Dyspnoea
Common	Throat tightness, throat irritation, cough
Uncommon	Tachypnoea
Gastrointestinal disorders:
Very common	Gastrointestinal discomfort
Common	Vomiting, nausea, oral discomfort
Uncommon	Abdominal distension, diarrhoea, faecal incontinence
Skin and subcutaneous tissue disorders:
Common	Hyperhidrosis
Uncommon	Erythema
Musculoskeletal and connective tissue disorders:
Common	Back, neck or jaw pain, pain in extremity, musculoskeletal discomfort
Uncommon	Arthralgia
General disorders and administration site conditions:
Very common	Chest pain
Common	Malaise, asthenia
Uncommon	Pain at injection site, general body pain

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 Rapiscan (see section 4.4). Adenosine receptor agonists, including Rapiscan, 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 Rapiscan administration; transient second degree AV block with one dropped beat was observed in one patient receiving Rapiscan. In postmarketing experience, third degree heart block and asystole have been reported within minutes of Rapiscan administration. Adenosine receptor agonists, including Rapiscan 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 Rapiscan 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. 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 was reported by 27% of subjects who received Rapiscan 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%).

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.

Aminophylline may be used to attenuate severe or persistent adverse reactions to Rapiscan (see section 4.4).

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB21 Mechanism of action Regadenoson is a low affinity agonist (Ki [?] 1.3 uM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 uM), 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 Rapiscan (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 Rapiscan administration is therefore greater in areas perfused by normal relative to stenosed arteries.

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 Rapiscan. 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 Rapiscan 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 Rapiscan 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 Rapiscan 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 Rapiscan 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 Rapiscan and placebo dosing, respectively. In the first and second studies, dyspnoea was reported as an adverse reaction following Rapiscan 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 Rapiscan (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 Rapiscan and placebo. Dyspnoea did not correlate with a decrease in FEV1.

Clinical studies have demonstrated the efficacy and safety of Rapiscan in patients indicated for pharmacologic stress radionuclide MPI. The efficacy and safety of Rapiscan 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 Rapiscan 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 b-blockers (18%), calcium channel blockers (9%), and nitrates (6%).

Comparison of the images obtained with Rapiscan 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 Rapiscan 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 Rapiscan 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 Rapiscan 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 Rapiscan 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.

In a study of adult patients undergoing pharmacological stress radionuclide MPI with Rapiscan, 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 Rapiscan. 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 Rapiscan 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 Rapiscan (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 Rapiscan; the incidence of headache (25% vs 16%) was more frequent with Rapiscan.

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

Pharmacokinetic properties

Rapiscan is administered by intravenous injection. 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 Rapiscan 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.

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 14C-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.

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. 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.

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).

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.

PHARMACEUTICAL PARTICULARS

List of excipients

Disodium phosphate dihydrate Sodium dihydrogen phosphate monohydrate Propylene glycol Disodium edetate Water for injections

Incompatibilities

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

Shelf life

Special precautions for storage

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.

Special precautions for disposal and other handling

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.

MARKETING AUTHORISATION HOLDER

Rapidscan Pharma Solutions EU Ltd. Regent's Place 338 Euston Road London NW1 3BT United Kingdom

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

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 - Rapiscan Agreement Rate (+- SE)	62 +- 2%	63 +- 3%	63 +- 2%
Number of Patients (n)	741	499	1,240
Rate Difference (Rapiscan - Adenosine) (+- SE)	1 +- 4%	-1 +- 5%	0 +- 3%
95% Confidence Interval	-7.5, 9.2%	-11.2, 8.7%	-6.2, 6.8%

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION