ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rapiscan 400 microgram solution for injection
2.
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.
Solution for injection
Clear, colourless solution.
4.
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.
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.
2
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 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.
•
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.
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
3
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 to
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.
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
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.
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.
4
Breast-feeding
It is unknown whether regadenoson is excreted in human breast milk. The excretion of regadenoson in
milk has not been studied in animals. A decision should be made whether to discontinue breast-
feeding or to abstain from 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).
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.
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 (≥ 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.
Psychiatric disorders:
Uncommon Anxiety, insomnia
Nervous system disorders:
Very common
Headache, dizziness
Common
Paraesthesia, hypoaesthesia, dysgeusia
Convulsions, syncope, transient ischaemic attack, unresponsiveness to stimuli,
depressed level of consciousness, tremor, somnolence
Uncommon
Eye disorders:
Uncommon Vision blurred, eye pain
Ear and labyrinth disorders:
Uncommon
Tinnitus
5
Cardiac disorders:
Very common
Electrocardiogram ST segment changes
Common
Angina pectoris, atrioventricular block, tachycardia, palpitations, other
ECG abnormalities including electrocardiogram QT corrected interval prolonged
Cardiac arrest, myocardial infarction, complete AV block, atrial
fibrillation/flutter, bradycardia
Uncommon
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.
6
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%).
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB21
Mechanism of action
Regadenoson is a low affinity agonist (K
i
≈ 1.3 µM) for the A
2A
adenosine receptor, with at least
10-fold lower affinity for the A
1
adenosine receptor (K
i
> 16.5 µM), and very low, if any, affinity for
the A
2B
and A
3
adenosine receptors. Activation of the A
2A
adenosine receptor produces coronary
vasodilation and increases coronary blood flow (CBF). Despite low affinity for the A
2A
adenosine
receptor, regadenoson has high potency for increasing coronary conductance in rat and guinea pig
isolated hearts, with EC
50
values of 6.4 nM and 6.7-18.6 nM, respectively. Regadenoson shows
selectivity (≥ 215-fold) for increasing coronary conductance (A
2A
-mediated response) relative to
slowing of cardiac AV nodal conduction (A
1
-mediated response) as measured by AV conduction time
(rat heart) or the S-H interval (guinea pig heart). Regadenoson preferentially increases blood flow in
coronary relative to peripheral (forelimb, brain, pulmonary) arterial vascular beds in the anaesthetised
dog.
Pharmacodynamic effects
Coronary blood 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
7
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 A
2B
and A
3
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 A
2B
and A
3
adenosine receptors. The incidence of
bronchoconstriction (FEV
1
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 FEV
1
.
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, 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 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 ≥ 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:
8
ADVANCE
MPI 1
(n = 1,113)
ADVANCE
MPI 2
(n = 758)
Combined
Studies
(n = 1,871)
Adenosine – Adenosine Agreement Rate (± SE)
Number of Patients (n)
61 ± 3%
372
64 ± 4%
259
62 ± 3%
631
Adenosine – Rapiscan Agreement Rate (± SE)
Number of Patients (n)
62 ± 2%
741
63 ± 3%
499
63 ± 2%
1,240
Rate Difference (Rapiscan – Adenosine) (± SE)
95% Confidence Interval
1 ± 4%
-7.5, 9.2%
-1 ± 5%
-11.2, 8.7%
0 ± 3%
-6.2, 6.8%
In ADVANCE MPI 1 and ADVANCE MPI 2, the Cicchetti-Allison and Fleiss-Cohen weighted
kappas of the median score of three blinded readers with respect to ischaemia size category (not
counting segments with normal rest uptake and mild/equivocal reduction in stress uptake as
ischaemic) for the combined studies of regadenoson with the adenosine scan were moderate, 0.53 and
0.61, respectively; as were the weighted kappas of two consecutive adenosine scans, 0.50 and 0.55,
respectively.
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
14
C-radiolabeled regadenoson to rats and dogs, most
radioactivity (85-96%) was excreted in the form of unchanged regadenoson. These findings indicate
that metabolism of regadenoson does not play a major role in the elimination of regadenoson.
Elimination
In healthy volunteers, 57% of the regadenoson dose is excreted unchanged in the urine
(range 19-77%), with an average plasma renal clearance around 450 ml/min, i.e., in excess of the
glomerular filtration rate. This indicates that renal tubular secretion plays a role in regadenoson
elimination.
9
Special populations
A population pharmacokinetic analysis including data from subjects and patients demonstrated that
regadenoson clearance decreases in parallel with a reduction in creatinine clearance (CLcr) and
increases with increased body weight. Age, gender, and race have minimal effects on the
pharmacokinetics of regadenoson.
Renal impairment
The disposition of regadenoson was studied in 18 subjects with various degrees of renal function and
in 6 healthy subjects. With increasing renal impairment, from mild (CLcr 50 to < 80 ml/min) to
moderate (CLcr 30 to < 50 ml/min) to severe renal impairment (CLcr < 30 ml/min), the fraction of
regadenoson excreted unchanged in urine and the renal clearance decreased, resulting in increased
elimination half-lives and AUC values compared to healthy subjects (CLcr ≥80 ml/min). However, the
maximum observed plasma concentrations as well as volumes of distribution estimates were similar
across the groups. The plasma concentration-time profiles were not significantly altered in the early
stages after dosing when most pharmacologic effects are observed. No dose adjustment is needed in
patients with renal impairment.
The pharmacokinetics of regadenoson in patients on dialysis has not been assessed.
Hepatic impairment
Greater than 55% of the regadenoson dose is excreted unchanged in the urine and factors that decrease
clearance do not affect the plasma concentration in the early stages after dosing when clinically
meaningful pharmacologic effects are observed. The pharmacokinetic parameters of regadenoson have
not been specifically evaluated in those with varying degrees of hepatic impairment. However,
post-hoc analysis of data from the two Phase 3 clinical trials showed that the pharmacokinetics of
regadenoson were not affected in a small subset of patients with laboratory values suggestive of
impaired hepatic function (2.5-fold transaminase elevation or 1.5-fold elevation of serum bilirubin or
prothrombin time). No dose adjustment is needed in patients with hepatic impairment.
Elderly patients
Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of
regadenoson. No dose adjustment is needed in elderly patients.
Paediatric population
The pharmacokinetic parameters of regadenoson have not yet been studied in the paediatric population
(< 18 years).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single and repeated dose toxicity, genotoxicity, or embryo-fetal development. Signs of
maternal and fetal toxicity were seen in rats and rabbits (reduced fetal weights, delays in ossification
[rats], reduced litter size and number of live fetuses [rabbits]), but not teratogenicity. Fetal toxicity was
noted following repeated daily administration of regadenoson, but at doses sufficiently in excess of the
recommended human dose. Fertility and pre- and post-natal studies have not been conducted.
6.
6.1 List of excipients
Disodium phosphate dihydrate
Sodium dihydrogen phosphate monohydrate
Propylene glycol
Disodium edetate
Water for injections
10
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
42 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.
Rapidscan Pharma Solutions EU Ltd.
Regent’s Place
338 Euston Road
London NW1 3BT
United Kingdom
8.
EU/1/10/643/001
9.
06/09/2010
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
11
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
12
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
County Cork
Ireland
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 6.0
presented in Module 1.8.1. of the Marketing Authorisation Application, is in place and
functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 1.1 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation Application and any
subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the EMA
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
Rapiscan 400 microgram solution for injection
Regadenoson
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each 5 ml vial contains 400 micrograms regadenoson (80 micrograms/ml).
3.
LIST OF EXCIPIENTS
Excipients: Disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate, propylene
glycol, disodium edetate, water for injections
See leaflet for further information.
4.
Solution for injection
1 vial of 400 micrograms
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For diagnostic use only.
Read the package leaflet before use.
Intravenous use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
Use product only in medical facilities with cardiac monitoring and resuscitation equipment.
8.
EXPIRY DATE
EXP
16
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Rapidscan Pharma Solutions EU Ltd.
Regent’s Place
338 Euston Road
London NW1 3BT
United Kingdom
EU/1/10/643/001
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
For single use only.
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
17
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
Rapiscan 400 microgram solution for injection
Regadenoson
Intravenous use
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
400 micrograms
6.
OTHER
18
B. PACKAGE LEAFLET
19
PACKAGE LEAFLET: INFORMATION FOR THE USER
Rapiscan 400 microgram solution for injection
Regadenoson
Read all of this leaflet carefully before you are given this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1.
What Rapiscan is and what it is used for
3.
How Rapiscan is given
4.
Possible side effects
5.
How to store Rapiscan
6.
Further information
1.
WHAT RAPISCAN IS AND WHAT IT IS USED FOR
Rapiscan contains the active substance,
regadenoson.
This belongs to a group of medicines called
‘coronary vasodilators’.
It makes the heart arteries expand and heart rate increase. This makes more
blood flow to the muscles of the heart.
This medicine is for diagnostic use only.
Rapiscan is used in a type of heart scan in adults called
‘myocardial perfusion imaging’.
The
scan uses a radioactive substance called a
‘radiopharmaceutical’
to create images. These images
show how well blood flows to the muscles of the heart. Usually, exercise on a treadmill is used to put
the heart under stress before a scan. During the exercise, a small amount of radiopharmaceutical is
injected into the body, often into a vein in the hand. Images are then taken of the heart. The doctor can
then see if the heart muscles are getting enough blood flow when it is under stress.
Rapiscan is used instead if someone is not able to exercise enough for the scan.
2.
BEFORE YOU ARE GIVEN RAPISCAN
Your doctor will not give you Rapiscan
-
if
you are allergic
(hypersensitive)
to regadenoson or any of the other ingredients of Rapiscan
listed in section 6 of this leaflet.
-
if you have
slow heart rate
(high degree heart block
or
sinus node disease)
, and don’t have a
pacemaker fitted.
-
if you have
chest pain
that occurs unpredictably
(unstable angina)
and that has not improved
after treatment.
-
if you have
low blood pressure
(hypotension)
.
-
if you have
heart failure.
Take special care with Rapiscan
Your doctor needs to know before you are given Rapiscan:
-
if you have had a
recent serious heart problem
(for example a heart attack or abnormal heart
rhythms).
-
if you have episodes of
heart block
(which can slow the heart down) or a
very slow heart rate.
20
-
Keep this leaflet. You may need to read it again.
2.
Before you are given Rapiscan
-
if you have a heart rhythm disorder called
long QT syndrome.
-
if you have any
heart
or
blood vessel condition,
particularly one that
gets worse
when your
blood pressure decreases. These include low blood volume
(caused, for example, by severe
diarrhoea or dehydration or taking water pills),
inflammation around the heart
(pericarditis)
and some forms of heart valve or artery disease
(for example, aortic or mitral stenosis).
- if you have
asthma
or
lung disease.
If any of these apply to you,
tell your doctor before the injection.
Children
Rapiscan should not be used in children below the age of 18 years.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines including
medicines obtained without prescription.
Particular care should be taken with the following medicines:
-
theophylline,
a medicine used to treat asthma and other lung diseases,
must not be used for at
least 12 hours before
you are given Rapiscan because it can block the effect of Rapiscan.
-
dipyridamole,
a medicine used to prevent blood clots,
must
not be used for at least two days
before
you are given Rapiscan because it can change the effect of Rapiscan.
Using Rapiscan with food and drink
Do not eat food or have drinks containing caffeine (for example, tea, coffee, cocoa, cola or chocolate)
for at least 12 hours before you are given Rapiscan. This is because caffeine can interfere with the
effect of Rapiscan.
Pregnancy and breast-feeding
Before you are given Rapiscan, tell your doctor:
-
if
you are pregnant
or think you are pregnant. There is no adequate information on the use of
Rapiscan in pregnant women. Harmful effects have been seen in animal studies but it is not
known if there is a risk to humans. Your doctor will only give you Rapiscan if it is clearly
necessary.
-
if
you are breast-feeding.
It is not known whether Rapiscan can pass into breast milk and will
only be given to you if your doctor thinks it is necessary. You should avoid breast-feeding for at
least 10 hours after you are given Rapiscan.
Ask your doctor for advice before using any medicine.
Driving and using machines
Rapiscan may make you feel dizzy. It may cause other symptoms (headache or shortness of breath)
that could affect your ability to drive or use machinery. These effects usually do not last longer than
30 minutes. Do not drive or operate machinery until these effects have improved.
Important information about some of the ingredients of Rapiscan
This medicine contains less than 1 mmol sodium (23 mg) per dose. After you have been given
Rapiscan, you will be given an injection of sodium chloride 9 mg/ml (0.9%) solution which contains
45 mg of sodium. To be taken into consideration if you are on a controlled sodium diet.
3.
HOW RAPISCAN IS GIVEN
Rapiscan is injected by a healthcare professional
(a doctor, nurse or medical technician) in a
medical facility where your heart and blood pressure can be monitored. It is injected directly into a
vein, as a single dose of 400 micrograms in a 5 ml solution – the injection will take about 10 seconds
to complete. The dose injected does not depend on your weight.
You will also be given
an injection of sodium chloride 9 mg/ml (0.9%) solution (5 ml), and an
injection of a small amount of a radioactive substance (radiopharmaceutical).
21
When you are given Rapiscan,
your heart rate will increase quickly. Your heart rate and blood
pressure will be monitored.
After the Rapiscan injection,
you will need to sit or lie down until your heart rate and blood pressure
return to your normal levels. The doctor, nurse or medical technician will let you know when you can
stand up.
A scan of your heart will be made after enough time has passed to allow the radiopharmaceutical to
reach the heart muscle.
If you are given more Rapiscan than you should
Some people have had flushing, dizziness and increased heart rate when they have been given too
much Rapiscan. If your doctor thinks that you are having severe side effects, or the effects of Rapiscan
are lasting too long, they may give you an injection of a medicine called aminophylline that reduces
these effects.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Rapiscan can cause side effects, although not everybody gets them.
The side effects are usually mild.
They normally start soon after the Rapiscan injection and are
usually over within 30 minutes.
They don’t usually need any treatment.
More serious side effects include:
-
sudden stopping of the heart or damage to the heart, heart block (a disorder of the heart’s
electrical signal, where the signal cannot pass from the upper to the lower chambers), rapid
heart beat
-
low blood pressure which may result in fainting or mini strokes (including weakness of the face
or an inability to speak)
Tell your doctor straight away if you think you are having severe side effects. Your doctor may then
give you an injection of a medicine called aminophylline that reduces these effects.
Very common side effects
(affects more than 1 user in 10)
-
headache, dizziness
-
shortness of breath
-
chest pain
-
changes in heart tracing tests (electrocardiogram)
-
flushing
-
discomfort in the stomach
Common side effects
(affects 1 to 10 users in 100)
-
heart pain (angina), abnormal heart rhythms, rapid heart beat, feeling the heart skipping a beat,
fluttering, or beating too hard or fast (palpitations)
-
low blood pressure
-
being sick (vomiting), feeling sick (nausea)
-
feeling unwell or weak
-
excessive sweating
-
pain in the back, arms, legs, neck or jaw
-
discomfort in the bones and muscles
-
pins and needles, reduced sensation, taste changes
-
discomfort in the mouth
22
-
throat tightness, throat irritation, cough
Uncommon side effects
(affects 1 to 10 users in 1,000)
-
sudden stopping of the heart or damage to the heart, heart block (a disorder of the heart’s
electrical signal, where the signal cannot pass from the upper to the lower chambers), slow heart
beat
-
fits, fainting, mini strokes (including weakness of the face or an inability to speak), reduced
responsiveness (which may include a comatose state), trembling, sleepiness
-
rapid breathing
-
high blood pressure, paleness, cold extremities
-
anxiety, difficulty sleeping
-
ringing in the ears
-
bloating, diarrhoea, involuntary loss of faeces
-
redness of the skin
-
pain in the joints
-
pain or discomfort around the area injected, body pain
If any side effects last longer than one hour or if they worry you (even side effects not listed in this
leaflet), tell a doctor or nurse.
5.
HOW TO STORE RAPISCAN
Keep out of the reach and sight of children.
Do not use Rapiscan after the expiry date which is stated on the vial and carton after EXP.
This medicine does not require any special storage conditions.
Do not use the solution if it is discoloured or particulate matter is present.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Rapiscan contains
The active substance in Rapiscan is regadenoson. Each 5 ml vial of Rapiscan contains 400 micrograms
of regadenoson.
The other ingredients are: disodium edetate, disodium phosphate dihydrate, sodium dihydrogen
phosphate monohydrate, propylene glycol, water for injections.
What Rapiscan looks like and contents of the pack
Rapiscan solution for injection is a clear, colourless solution with no particles visible. Rapiscan is
supplied in a carton containing a single use 5 ml glass vial with a rubber stopper and aluminium sealed
cap.
23
-
blurred vision, eye pain
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Rapidscan Pharma Solutions EU Ltd.
Regent’s Place
338 Euston Road
London NW1 3BT
United Kingdom
Manufacturer:
Gilead Sciences Limited
IDA Business & Technology Park
Carrigtohill
County Cork
Ireland
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
The following information is intended for medical or healthcare professionals only:
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 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.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
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.
For further information, please refer to the complete Summary of Product Characteristics enclosed
with the pack.
24
Source: European Medicines Agency
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