1. Name Of The Medicinal Product
Rapiscan 400 microgram solution for injection
2. Qualitative And Quantitative Composition
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.
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 as a pharmacological stress agent for radionuclide myocardial perfusion imaging (MPI) in adult patients unable to undergo adequate exercise stress.
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 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.
Repeated use
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.
Paediatric population
The safety and efficacy of Rapiscan 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.
• 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 radiopharmaceutical for the myocardial perfusion imaging agent should be administered10-20 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.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients (see 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
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.
Myocardial ischaemia
Fatal cardiac arrest, life-threatening ventricular arrhythmias, and myocardial infarction may result from the ischaemia induced by pharmacologic stress agents like regadenoson.
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.
Bronchoconstriction
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 Rapiscan 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 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.
4.5 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) injected1 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 pulsedwave Doppler ultrasonography. Aminophylline has been used to attenuate adverse reactions to Rapiscan (see section 4.4).
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 Rapiscan administration (see section 4.2).
Cardioactive medicinal products
In clinical studies, Rapiscan was administered to patients taking other cardioactive medicinal products (i.e., β-blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, and angiotensin receptor blockers) without apparent effects on the safety or efficacy profile of Rapiscan.
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.
4.6 Pregnancy And Lactation
Pregnancy
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.
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 breastfeeding 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.
Fertility
Fertility studies with Rapiscan have not been performed (see section 5.3).
4.7 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.
4.8 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). 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 (
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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 (versus < 1%).
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 Rapiscan (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 μM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 μM), and very low, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor produces coronary vasodilation and increases coronary blood flow (CBF). Despite low affinity for the A2A adenosine receptor, regadenoson has high potency for increasing coronary conductance in rat and guinea pig isolated hearts, with EC50 values of 6.4 nM and 6.7-18.6 nM, respectively. Regadenoson shows selectivity (
Pharmacodynamic effects
Coronary blood 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 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.
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 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).
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 bronchoconstriction (FEV1 reduction > 15% from baseline) after Rapiscan administration was assessed in two randomised, controlled clinical studies. In the first study in 49 patients with moderate to severe COPD, the rate of bronchoconstriction 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 bronchoconstriction was the same (4%) following both Rapiscan and placebo dosing. In both 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. Dyspnoea did not correlate with a decrease in FEV1.
Clinical efficacy
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, doubleblind 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 β-blockers (18%), calcium channel blockers (9%), and nitrates (6%).
Image agreement
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
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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.
Safety and tolerability testing
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.
Paediatric population
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).
5.2 Pharmacokinetic Properties
Absorption
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.
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 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.
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.
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
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
48 months
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 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.
7. Marketing Authorisation Holder
Rapidscan Pharma Solutions EU Ltd.
Regent's Place
338 Euston Road
London NW1 3BT
United Kingdom
8. Marketing Authorisation Number(S)
EU/1/10/643/001
9. Date Of First Authorisation/Renewal Of The Authorisation
06/09/2010
10. 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
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