Regadenoson (Rapiscan®) : RMP summary€¦ · The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate

RAPISCAN (REGADENOSON)

Generic name: Rapiscan

Active substance: Regadenoson

Dosage levels: One level, no adjustment needed

Single injection of 400 micrograms regadenoson (5 ml)

Galenic form: Solution for injection

SUMMARY OF RISK MANAGEMENT PLAN

Version 10

Date of report: 26 September 2017

Marketing Authorisation Holder:

Rapidscan Pharma Solutions EU Ltd.,

Marketing authorisation currently being transferred to

GE Healthcare AS, P.O.Box 4220 Nydalen, N-0401 Oslo, Norway

Disclaimer:

The Risk Management Plan (RMP) is a comprehensive document submitted as part of the

application dossier for market approval of a medicine. The RMP summary contains

information on the medicine's safety profile and explains the measures that are taken in order

to further investigate and follow the risks as well as to prevent or minimise them.

GE Healthcare September 2017

Global Pharmacovigilance

Page 2 of 45

The RMP summary of Rapiscan is a concise document and does not claim to be exhaustive.

As the RMP is an international document, the summary might differ from the

"Arzneimittelinformation / Information sur le médicament" approved and published in

Switzerland, e. g. by mentioning risks occurring in populations or indications not included in

the Swiss authorization.

Please note that the reference document which is valid and relevant for the effective and safe

use of Rapiscan in Switzerland is the "Arzneimittelinformation/ Information sur le

médicament" (see www.swissmedic.ch) approved and authorized by Swissmedic. GE

Healthcare is fully responsible for the accuracy and correctness of the content of the published

summary RMP of Rapiscan.



Page 3 of 45

PART VI: SUMMARY OF THE RISK MANAGEMENT PLAN BY PRODUCT

VI.1 Elements for summary tables in the EPAR

VI.1.1 Summary table of Safety concerns

Table 37 Summary of safety concerns

Important identified risk SA/AV nodal block

Myocardial ischemia

Hypotension

Hypersensitivity

Seizures

Prolongation of regadenoson-induced seizures following administration

of aminophylline

Worsening/recurrence of atrial fibrillation

Elevated blood pressure and hypertensive crisis

Cerebrovascular accident (CVA, stroke)

Interaction with dipyridamole

Respiratory compromise (bronchoconstriction and respiratory arrest)

Important potential risk Off-label use involving exercise

Missing information Safety in children

Safety in pregnancy

Safety in lactation

Safety in patients with severe hepatic impairment

Safety in patients with prolonged QT syndrome

VI.1.2 Table of on-going and planned studies in the Post-authorisation

Pharmacovigilance Development Plan

There is no on-going or planned post authorization study.



Page 4 of 45

Summary of Post authorisation efficacy development plan

Table 38 Summary of Post authorisation efficacy development plan

Study (type and

study number)

Objectives Efficacy

uncertainties

addressed

Status (planned,

started)

Date for submission

of interim or final

reports

3606-CL-3004 To demonstrate that

the strength of

agreement between

single photon

emission computed

tomography (SPECT)

imaging with

regadenoson

following inadequate

exercise stress testing

and SPECT imaging

with regadenoson

alone is not inferior to

the strength of

agreement between

two sequential

regadenoson SPECT

images without

exercise and to assess

the safety and

tolerability of

regadenoson

administered during

recovery exercise

The efficacy of

regadenoson in

combination with

exercise SPECT MPI

to detect Myocardial

perfusion defects is

not meaningfully

different from

Regadenoson supine

SPECT MPI study.

Completed Redacted synopsis

Nov 2015.

Table 39 Summary of risk minimisation measures

Safety concern Routine risk minimisation measures Additional risk

minimisation measures

SA/AV Nodal Block SPC information that is relevant to minimizing the

risk of SA/AV Nodal Block is presented below.

None proposed

Section 4.2 Posology and Method of

Administration



Page 5 of 45




Treatment with Rapiscan is restricted to use in a

medical facility where cardiac monitoring and

resuscitation equipment are available.

Aminophylline may be used to attenuate severe and/or

persistent adverse reactions to Rapiscan but should

not be used solely for the purpose of terminating a

seizure induced by Rapiscan.

Rapiscan causes a rapid increase in heart rate. Patients

should remain sitting or lying down and be monitored

at frequent intervals after the injection until ECG

parameters, heart rate and blood pressure has returned

to pre-dose levels.

Section 4.3 Contraindications

• Second or third degree atrioventricular (AV)

block or sinus node dysfunction, unless these patients

have a functioning artificial pacemaker.

Section 4.4 Special Warnings and Precautions for

Use

Rapiscan has the potential to cause serious and life

threatening reactions, including those listed below.

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

but should not be used solely for the purpose of

terminating a seizure induced by Rapiscan.

Sinoatrial and atrioventricular nodal block

Adenosine receptor agonists including regadenoson

can depress the sinoatrial and AV nodes and may



Page 6 of 45




cause first, second or third degree AV block, or sinus

bradycardia.

Myocardial ischaemia

Fatal cardiac arrest, life-threatening ventricular

arrhythmias, and myocardial infarction may result

from the ischaemia induced by pharmacologic stress

agents like Rapiscan

Rapiscan should be used in caution in patients with

recent myocardial infarction. Clinical trials conducted

with regadenoson excluded patients with recent

(within 3 months) myocardial infarction.

Section 4.8 Undesirable Effects

Summary of safety profile

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, elevated blood pressure

leading to hypertension and hypertensive crises, and

SA/AV node block leading to first, second or third

degree AV block, or sinus bradycardia requiring

intervention (see section 4.4). Signs of

hypersensitivity (rash, urticaria, angioedema,

anaphylaxis and/or throat tightness) may be

immediate or delayed onset. Aminophylline may be

used to attenuate severe or persistent adverse reactions

to Rapiscan but should not be used solely for the

purpose of terminating a seizure induced by Rapiscan

(see section 4.4).

Tabulated summary of adverse reactions

Cardiac Disorders:

Common: Atrioventricular block



Page 7 of 45




Uncommon: Cardiac arrest, Complete AV block,

Bradycardia

Description of selected adverse reactions

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.

Regadenoson is only administered in a hospital or

clinic setting by a health care professional and is

restricted to use in a medical facility where cardiac

monitoring and resuscitation equipment are available.

It is available as a prescription only medicine. The

SPC also states that aminophylline can be used to

attenuate severe and/or persistent adverse reactions to

Rapiscan but should not be used solely for the purpose

of terminating a seizure induced by Rapiscan.

Myocardial Ischemia SPC information that is relevant to minimizing the

risk of myocardial ischemia is presented below.

None proposed


Administration










Page 8 of 45








to pre-dose levels.


Unstable angina that has not been stabilised with

medical therapy.

Section 4.4 Special Warnings and Precautions for

Use



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 Rapiscan

Rapiscan should be used in caution in patients with

recent myocardial infarction. Clinical trials conducted

with regadenoson excluded patients with recent

(within 3 months) myocardial infarction.

Hypotension SPC information that is relevant to minimizing the

risk of hypotension is presented below.

None proposed



Page 9 of 45





Administration












to pre-dose levels.


Severe hypotension.

Decompensated states of heart failure.

Section 4.4 Special Warnings and Precautions

for Use



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


purpose of terminating a seizure induced by

Rapiscan.



Page 10 of 45




Hypotension


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.


Summary of the safety profile






leading to hypertension and hypertensive crises,

and SA/AV node block leading to first, second or

third degree AV block, or sinus bradycardia

requiring intervention (see section 4.4). Signs of

hypersensitivity (rash, urticaria, angioedema,

anaphylaxis and/or throat tightness) may be

immediate or delayed onset. Aminophylline may be

used to attenuate severe or persistent adverse

reactions to Rapiscan but should not be used solely

for the purpose of terminating a seizure induced by

Rapiscan (see section 4.4).


Nervous system disorders: Very common: dizziness

Uncommon: Syncope

Rare: Cerbrovascular attack Vascular disorders:

Common: Hypotension


Adenosine receptor agonists, including Rapiscan

induce arterial vasodilation and hypotension. In



Page 11 of 45




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.

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 = 1016), but

had a higher incidence of hypotension (2% versus <

1%).

Section 5.1 Pharmacodynamic properties

Pharmacodynamic effects

Haemodynamic effects

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.




monitoring and resuscitation equipment are

available. It is available as a prescription only

medicine. The SPC also states that aminophylline

can be used to attenuate severe and/or persistent

adverse reactions to Rapiscan.



Page 12 of 45




Interaction with

dipyridamole

SPC information that is relevant to minimizing the

risk of the interaction with dipyridamole is

presented below.

None proposed

Section 4.2 Posology and method of

administration

Posology

When possible, dipyridamole should be withheld

for at least two days prior to Rapiscan

administration.

Section 4.5 Interaction with other medicinal

products and other forms of interaction

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.

Patients are advised not to take any medications

containing dipyridamole for at least two days prior

to Rapiscan administration. It is available as a

prescription only medicine. The SPC also states

that aminophylline can be used to attenuate severe

and/or persistent adverse reactions to Rapiscan.

Hypersensitivity SPC information that is relevant to minimizing the

risk of the hypersensitivity is presented below.

None proposed


Hypersensitivity to the active substance or to any of

the excipients.

Section 4.8 Summary of safety profile




Page 13 of 45




Signs of hypersensitivity (rash, urticaria,

angioedema, anaphylaxis and/or throat tightness)

may be immediate or delayed onset.


Immune system disorders:

Uncommon: Hypersensitivity reactions including

rash, urticaria, angioedema, and anaphylaxis








adverse reactions to Rapiscan but should not be

used solely for the purpose of terminating a seizure

induced by Rapiscan.

Seizures SPC information that is relevant to minimizing the

potential risk of seizure is presented below.

None proposed


administration




Aminophylline may be used to attenuate severe

and/or persistent adverse reactions to Rapiscan but

should not be used solely for the purpose of


Section 4.4 Special warnings and precautions for

use







Page 14 of 45











Rapiscan.

Risk of seizure

Caution should be used when administering

Rapiscan to patients with a history of seizures or

other risk factors for seizures, including the

concomitant administration of medicinal products

that lower seizure threshold (e.g. antipsychotics,

antidepressants, theophyllines, tramadol, systemic

steroids and quinolones).

Aminophylline may prolong a seizure or cause

multiple seizures because of its proconvulsant

effect. Therefore administration of aminophylline

solely for the purpose of terminating a seizure

induced by Rapiscan is not recommended.

Section 4.8 Undesirable effects


Aminophylline may be used to attenuate severe or



seizure induced by Rapiscan (see section 4.4).


Nervous system disorders

Uncommon: Convulsions, tremor







Page 15 of 45





medicine.

Prolongation of

regadenoson-induced

seizures following

administration of

aminophylline


potential risk of prolongation of regadenoson-

induced seizures following administration of

aminophylline is presented below.

Completed - DHPC

communication of the risk

and the relevant clinical

actions that is required to

minimise the occurrences of

such cases.


administration










Rapiscan.


use












Rapiscan.

Risk of seizure





Page 16 of 45





concomitant administration of medicinal products

that lower seizure threshold (e.g. antipsychotics,

antidepressants, theophyllines, tramadol, systemic

steroids and quinolones).



effect. Therefore administration of aminophylline

solely for the purpose of terminating a seizure

induced by Rapiscan is not recommended.








Nervous system disorders

Uncommon: Convulsions, tremor






medicine.

Worsening/recurrence

of atrial fibrillation


potential risk of worsening/recurrence of atrial

fibrillation is presented below.

None proposed


administration



Page 17 of 45












use












Rapiscan.

Atrial fibrillation or flutter

Rapiscan should be used with caution in patients

with a history of atrial fibrillation or flutter. In

postmarketing experience there have been cases of

worsening or recurrence of atrial fibrillation after

administration of Rapiscan.




(potentially associated with fatal cardiac arrest,

lifethreatening ventricular arrhythmias, and

myocardial infarction), hypotension leading to

syncope and transient ischaemic attacks, elevated

blood pressure leading to hypertension and

hypertensive crises, and SA/AV node block leading



Page 18 of 45




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



induced by Rapiscan (see section 4.4).

Elevated blood

pressure and

hypertensive crisis


potential risk of elevated blood pressure is

presented below.

None proposed


administration









use












Rapiscan.

Elevated blood pressure



Page 19 of 45




Rapiscan may cause clinically significant increases

in blood pressure, which in some patients can lead

to hypertensive crisis (see section 4.8). The risk of

significant increases in blood pressure may be

higher in patients with uncontrolled hypertension.

Consideration should be given to delaying Rapiscan

administration until blood pressure is well

controlled.




(potentially associated with fatal cardiac arrest,

lifethreatening ventricular arrhythmias, and

myocardial infarction), hypotension leading to

syncope and transient ischaemic attacks, elevated

blood pressure leading to hypertension and

hypertensive crises, and SA/AV node block

leading to first, second or third degree AV block, or

sinus bradycardia requiring intervention (see

section 4.4). Signs of hypersensitivity (rash,

urticaria, angioedema, anaphylaxis and/or throat

tightness) may be immediate or delayed onset.






Vascular disorders Uncommon: hypertension


In clinical trials, increased systolic blood pressure

(≥ 50 mm Hg) was observed in 0.7% of patients

and increased diastolic blood pressure (≥ 30 mm

Hg) in 0.5% of patients. Most increases resolved

within 10 to 15 minutes, but in some cases,

increases were observed at 45 minutes following

administration.



Page 20 of 45














CVA (Stroke) SPC information that is relevant to minimizing the

potential risk of CVA is presented below.

Completed - DHPC

communication of the risk

and the relevant clinical

actions that is required to

minimise the occurrences of

such cases.


administration









use













Page 21 of 45





Rapiscan.

Hypotension


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


Atrial fibrillation or flutter


with a history of atrial fibrillation or flutter. In

postmarketing experience there have been cases of

worsening or recurrence of atrial fibrillation after


Elevated blood pressure

Rapiscan may cause clinically significant increases

in blood pressure, which in some patients can lead

to hypertensive crisis (see section 4.8). The risk of

significant increases in blood pressure may be

higher in patients with uncontrolled hypertension.

Consideration should be given to delaying Rapiscan

administration until blood pressure is well

controlled.

Transient ischaemic attacks and cerebrovascular

accident

Rapiscan can cause transient ischaemic attack (see

section 4.8). In post-marketing experience there

have also been reports of cerebrovascular accident

(CVA).




Page 22 of 45










leading to hypertension and hypertensive crises,

and SA/AV node block leading to first, second or

third degree AV block, or sinus bradycardia

requiring intervention (see section 4.4).


Nervous system disorders Uncommon: transient

ischemic attack. Rare: cerebrovascular accident


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.

In clinical trials, increased systolic blood pressure

(≥ 50 mm Hg) was observed in 0.7% of patients

and increased diastolic blood pressure (≥ 30 mm

Hg) in 0.5% of patients. Most increases resolved

within 10 to 15 minutes, but in some cases,

increases were observed at 45 minutes following

administration.



Page 23 of 45














Respiratory

compromise

(bronchoconstriction

and respiratory arrest)


potential risk of respiratory compromise is

presented below.

None proposed


administration









use












Rapiscan.



Page 24 of 45




Bronchoconstriction

Adenosine receptor agonists, including Rapiscan,

may cause bronchoconstriction and respiratory

arrest (see Section 4.8), especially in patients with

known or suspected bronchoconstrictive disease,

chronic obstructive pulmonary disease (COPD) or

asthma. Appropriate bronchodilator therapy and

resuscitative measures should be available prior to

Rapiscan administration.



Respiratory, thoracic and mediastinal disorders:

Uncommon: Wheezing

Not known: Bronchospasm and respiratory arrest

Section 5.1 Pharmacodynamic properties

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



Page 25 of 45




COPD; 34% for patients with asthma) while no

subjects experienced dyspnoea following placebo

dosing. Dyspnoea did not correlate with a decrease

in FEV1.











Off label use

involving exercise


potential risk of off label use involving exercise is

presented below.

Post-marketing safety

assessment of regadenoson

in combination with

exercise (3606-CL- 3004) is

completed.

4.2 Posology and method of administration

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 has

returned to pre-dose levels.


use

Rapiscan has the potential to cause serious and life-












Page 26 of 45





Rapiscan.

Combination with exercise

Use of Rapiscan involving exercise has been

associated with serious adverse reactions including

hypotension, hypertension, syncope and cardiac

arrest. Patients who have had any symptoms or

signs suggestive of acute myocardial ischaemia

during exercise or recovery are likely to be at

especially high risk of serious adverse reactions.








adverse reactions to Rapiscan.

Safety in Children SPC information that is relevant to the lack of

safety information in children is presented below.

The EMA has adopted a

Decision granting a

Paediatric Investigation

Plan (PIP) for regadenoson

in the diagnosis of

myocardial perfusion

disturbances and a deferral

of studies in all paediatric

age groups (24 April 2009;

EMEA-000410-PIP01-08;

P/82/2009). A modification

to the PIP has been adopted

by the Paediatric Committee

(PDCO) on 17 Oct 2013

(EMEA-00410-PIP01-08-

M01) to change exclusion

criteria to enhance the

probability of subject

enrolment and to remove

the requirement to enrol

neonates since the

assessment of myocardial



Page 27 of 45




perfusion disturbances in

this age group


Administration

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.

Section 5.2 Pharmacokinetic properties

Paediatric population

The pharmacokinetic parameters of regadenoson

have not yet been studied in the paediatric

population (< 18 years).

Regadenoson is available as a prescription only

medicine.

Safety in Pregnancy SPC information that is relevant to the lack of

safety information in pregnancy is presented below.

None proposed

Section 4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of

regadenoson in pregnant women. Animal studies on

pre- and post-natal development have not been

conducted. Fetotoxicity, but not teratogenicity, was

noted in embryo-foetal development studies. The

potential risk for humans is unknown. Rapiscan

should not be used during pregnancy unless clearly

necessary.

Section 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,



Page 28 of 45




genotoxicity, or embryo-foetal development. Signs

of maternal and foetal toxicity were seen in rats and

rabbits (reduced foetal weights, delays in

ossification [rats], reduced litter size and number of

live foetuses [rabbits]), but not teratogenicity.

Foetal 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.


medicine

Safety in lactation SPC information that is relevant to the lack of

safety information in lactation is presented below.

None proposed

Section 4.6 Fertility, pregnancy and lactation

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.


medicine

Safety in patients

with severe hepatic

impairment

SPC information that is relevant to the lack of

safety information in patients with hepatic

impairment is presented below.

A two part, non-

interventional, post-

authorization safety study

(PASS) to assess the safety

profile of Rapiscan

(regadenoson) in patients

with liver impairment and to

observe common adverse



Page 29 of 45




events reported in the post

marketing setting (01-1-401)

was conducted. The

objectives of study 01-1-401

were for part A to assess the

safety profile (changes in

haemodynamics, frequency

and severity of adverse

events) of regadenoson (0.4

mg/5 mL intravenous (IV)

bolus) in patients with end-

stage liver disease (ESLD)

compared with matched

controls without liver

disease, using retrospective

medical record review and

for part B to prospectively

collect safety information in

a real-life, post-marketing

setting, in patients with a

clinical indication for a

pharmacological stress


imaging (MPI) study, with

commercially available

regadenoson (0.4 mg/5 mL

IV bolus) to determine or

characterize the common

adverse drug reactions

(ADRs).

Regadenoson was well

tolerated in patients with

ESLD and there were no

new or unexpected safety

concerns.


Administration

Posology

Hepatic impairment



Page 30 of 45




No dose adjustment is necessary.

Section 5.2 Pharmacokinetic properties

Hepatic impairment

Greater than 55% of the regadenoson dose is

excreted unchanged in the urine and factors that

decrease clearance does 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.


medicine

Safety in patients

with prolonged QT

syndrome

SPC information which is relevant to the lack of

safety information in patients with prolonged QT

syndrome is presented below

None proposed


use

Long QT syndrome

Regadenoson stimulates sympathetic output and

may increase the risk of ventricular

tachyarrhythmias in patients with a long QT

syndrome.



Cardiac Disorders:

Common: Other ECG abnormalities including

electrocardiogram QT corrected interval prolonged




Page 31 of 45




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.













Page 32 of 45

VI.2 Elements for a Public Summary

VI.2.1 Overview of disease epidemiology

Coronary artery disease (CAD) is a progressive disease that can cause blockage of the

vessels that supply blood and nutrition to the heart. This process results in myocardial

ischemia, which can cause chest pain, angina and myocardial infarction (or “heart attack”).

Approximately 3 million people in the EU are affected by CAD, who requires diagnostic

tests to determine the presence, location and severity of their disease.

Myocardial perfusion imaging (MPI) is a non-invasive diagnostic procedure that

determines the functional consequence of an obstruction resulting from coronary artery

disease. When combined with single-photon emission computed tomography, MPI

facilitates the diagnosis of coronary artery disease, assesses the risk of future cardiac

events, and guides clinical decisions regarding medical treatment, revascularisation or

urgent intervention.

Fractional flow reserve (FFR) is a technique used in coronary catheterization to measure

pressure differences across a coronary artery stenosis (narrowing, usually due to plaque build-

up) to determine the likelihood that the stenosis impedes oxygen delivery to the heart muscle

(myocardial ischemia).

Regadenoson is a selective coronary vasodilator for use as a pharmacological stress agent

for radionuclide MPI in adult patients unable to undergo adequate exercise stress and for

the measurement of FFR of coronary artery stenosis of unknown functional significance in

adult patients

VI.2.1 Summary of treatment benefits

A total of 3,142 patients have been dosed to regadenoson in thirteen clinical trials: 1,684

of these patients were enrolled in the Phase 3 studies (ADVANCE MPI 1 and 2 studies

and 3606-CL-3002) in the target population of patients with a clinical indication for

pharmacological stress radionuclide myocardial perfusion imaging, and 1,006 patients

were enrolled in the Phase 4 studies examining the safety and tolerance of regadenoson in

subjects with asthma or chronic obstructive pulmonary disease (COPD; study 3606-CL-

3001) or renal impairment (study 3606-CL-3010). The pivotal Phase 3 trials tested the

safety and efficacy of regadenoson compared to adenosine in patients clinically indicated

to undergo a pharmacological stress myocardial perfusion imaging study. The ADVANCE

MPI 1 and ADVANCE MPI 2 studies, individually and combined, demonstrated that

Rapiscan is effective in assessing the extent of reversible myocardial perfusion

abnormalities, which is used to diagnose coronary artery disease. Although the knowledge

of the safety of regadenoson continues to increase with its use in clinical practice, in the

phase 3 trials some adverse reactions appeared less frequently with regadenoson than

adenosine (chest pain, flushing and ‘throat neck and jaw pain’) and some adverse reactions

(headache) were higher with regadenoson than adenosine.



Page 33 of 45

FFR measurements obtained with regadenoson are nearly identical to the pharmacological

stress agent adenosine. Although adenosine has been established clinically as the gold

standard for the measurement of FFR to guide percutaneous coronary intervention,

adenosine is not approved for this use. Although the use of FFR to guide coronary

intervention has been demonstrated to improve patient outcomes (death, myocardial

infarction, and urgent revascularization) and health resource utilization {Fearon 2010},

there is no pharmacological stress agent approved for use to cause maximum hyperaemia

during the measurement of FFR. Thus, a significant unmet medical need exists for a

regadenoson to be indicated for the measurement of FFR.

Regadenoson provides a more convenient mode of administration, and a less error-prone

dosing alternative to the other vasodilator stress agents currently used in radionuclide MPI

procedures and for the measurement of FFR, and may prove to be better tolerated than

adenosine.

VI.2.2 Unknowns relating to treatment benefits

Insufficient information exists using Rapiscan for the diagnosis of coronary artery disease

in children or in women who are pregnant or breast feeding. There is insufficient

information regarding the use of Rapiscan in patients with prolonged QT interval.

VI.2.3 Summary of safety concerns

Important identified risks

Risk What is known Preventability

Heart block

(SA/ AV 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.

Regadenoson is only administered in a hospital

or clinic setting by a health care professional

and is restricted to use in a medical facility

where cardiac monitoring and resuscitation

equipment are available. It is available as a

prescription only medicine. The SPC also states

that aminophylline can be used to attenuate

severe and/or persistent adverse reactions to

Rapiscan.

Heart attack

(Myocardial

ischaemia)

Fatal cardiac arrest, life-threatening

ventricular arrhythmias, and myocardial

infarction may result from the ischaemia

induced by pharmacologic stress agents

like regadenoson.





equipment are available. The SPC states that

aminophylline can be used to attenuate severe




Page 34 of 45


Interaction with

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

Patients are advised to not take any medications

containing dipyridamole for at least two days

prior to Rapiscan administration. The SPC states



Rapiscan.

Allergy

(Hypersensitivity)

An allergic reaction, which can cause

rash, wheals/wheals, swelling under the

skin near the eyes or throat, throat

tightness, and difficulty in breathing may

occur immediately or have delayed onset

after Rapiscan injection.





equipment are available. . The SPC states that

aminophylline can be used to attenuate


Rapiscan.

Low blood pressure

(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


Blood pressure and heart rate should be

measured at frequent intervals.





equipment are available. The SPC also states



Rapiscan.

Elevated blood

pressure

(Hypertension,

hypertensive crisis)

Administration of adenosine receptor

agonists, including Rapiscan, may result

in clinically significant

increases in blood pressure in some

patients. Among patients who experienced

an increase in blood pressure in clinical

trials, the increase was observed within

minutes of Rapiscan administration. Most

increases resolved within 10 to 15

minutes, but in some cases, increases were

observed at 45 minutes following

administration. In post-marketing

experience, cases of potentially clinically

significant hypertension have been

reported, particularly with underlying

hypertension and when low-level exercise

was included.


measured at frequent intervals.

Regadenoson is only administered in a

hospital or clinic setting by a health care

professional and is restricted to use in a medical

facility where cardiac monitoring and

resuscitation equipment are available. The SPC

also states that aminophylline can be used to

attenuate severe and/or persistent adverse

reactions to Rapiscan.

Brain attack, stroke Risk factors for stroke and transient

ischemic attack (mini-stroke) include


measured at frequent intervals. Patients should



Page 35 of 45


(transient ischemic

attacks and

cerebrovascular

accident, CVA)

hypertension, diabetes mellitus, smoking,

and dyslipidaemia – factors also

associated with coronary artery disease

and will therefore be prevalent in the

population undergoing a pharmacological

stress myocardial perfusion imaging

study.

Rapiscan may cause an increase in blood

pressure, a decrease in blood pressure

(also called hypotension) and atrial

fibrillation, each of which are risk factors

for a brain attack (stroke). Rarely,

Rapiscan can cause a stroke.

remain sitting or lying down and be monitored

at frequent intervals after the injection until the

ECG parameters, heart rate and blood pressure

has returned to pre-dose levels. Rapiscan should

only be used in a medical facility where

monitoring and resuscitative equipment are

available.

Aminophylline can be used to attenuate severe

and/or persistent adverse reactions to Rapiscan

Seizures Rapiscan is an adenosine receptor agonist

with selectivity for the adenosine A2A

receptor over the adenosine A1 receptor.

Adenosine A2A receptors may have a role

in controlling the evolution of seizures by

lowering seizure threshold.




concomitant administration of medicinal

products that lower seizure threshold (e.g.

antipsychotics, antidepressants, theophyllines,

tramadol, systemic steroids and quinolones).

Prolongation of

regadenoson- induced

seizures following

administration of

aminophylline

Administration of aminophylline has been

associated with seizures.

Aminophylline may also be used to

attenuate other severe and persistent

adverse reactions after Rapiscan

administration. The efficacy and safety of

intravenous aminophylline in the

treatment of seizures induced by Rapiscan

have not been assessed.



effect. Therefore, caution should be exercised

when considering administration of

aminophylline solely for the purpose of


Worsening/

recurrence of atrial

fibrillation

Regadenoson may cause direct

stimulation of the sympathetic nervous

system and release epinephrine and

norepinephine, which in turn may result in

deterioration of pre-existing atrial

fibrillation. In post-marketing experience,

there have been cases of worsening or

recurrence of atrial fibrillation after



with a history of atrial fibrillation or flutter.





equipment are available.

Aminophylline can be used to attenuate severe




Page 36 of 45


Respiratory

compromise

(bronchoconstriction

and respiratory arrest)

Adenosine receptor agonists, including

Rapiscan, may cause respiratory

compromise (bronchoconstriction and

respiratory arrest), especially in patients

with known or suspected

bronchoconstrictive disease, chronic

obstructive pulmonary disease (COPD) or

asthma. Appropriate bronchodilator

therapy and resuscitative measures should

be available prior to Rapiscan

administration. In post-marketing

experience incidences of respiratory

compromise (bronchoconstriction and

respiratory arrest) was due to a history of

COPD/asthma. None of these cases

resulted in serious complications such as

respiratory arrest, intubation or a fatal

outcome. Bronchocontriction and

respiratory arrest should be carefully

monitored.

Appropriate bronchodilator therapy and

resuscitative measures should be available prior

to Rapiscan administration.


Rapiscan to patients with a history of

COPD/asthma.

Important potential risks

Risk What is known (Including reason why it is considered a potential risk)

Use in combination with

exercise

In most patients, Rapiscan causes a rapid increase in heart rate and may also increase

blood pressure. Exercise may also increase heart rate and blood pressure, which if

combined may raise these parameters to unsafe levels. 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 has returned to pre-dose levels.

Missing information

Risk What is known

Limited information on

safety in 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-foetal development studies (see section

5.3). The potential risk for humans is unknown. Rapiscan should not be used during

pregnancy unless clearly necessary.



Page 37 of 45

Risk What is known


safety in lactation

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.


safety in children

The pharmacokinetic parameters of regadenoson have not yet been studied in the

paediatric population (< 18 years).


safety in patients with

severe hepatic impairment

Greater than 55% of the regadenoson dose is excreted unchanged in the urine and

factors that decrease clearance does 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). A completed

PAS study also reported that regadenoson was well tolerated in patients with ESLD

and there were no new or unexpected safety concerns. No dose adjustment is needed

in patients with hepatic impairment.


safety in patients with

prolonged QT syndrome

Regadenoson stimulates sympathetic output and may increase the risk of ventricular

tachyarrhythmias in patients with a long QT syndrome.

VI.2.4 Summary of risk minimisation measures by safety concern

All medicines have a Summary of Product Characteristics (SPC) that provides physicians,

pharmacists and other health care professionals with details on how to use the medicine,

the risks and recommendations for minimising them. An abbreviated version of this in lay

language is provided in the form of the package leaflet (PL). The measures in these

documents are known as routine risk minimisation measures.

The Summary of Product Characteristics and the Package leaflet for Rapiscan

(regadenoson) can be found in the Rapiscan’s EPAR page.

A Direct Healthcare Professional Communication (DHPC) was issued to communicate the

identified risk of cerebrovascular accident and the risk of aminophylline prolongation of

regadenoson-induced seizure and the relevant clinical actions to minimize these

occurrences

This medicine has special conditions and restrictions for its safe and effective use

(additional risk minimisation measures). Full details on these conditions and the key



Page 38 of 45

elements of any educational material can be found in Annex II of the product information

which is published in Rapiscan’s EPAR page; how they are implemented in each country

however will depend upon agreement between the manufacturer and the national

authorities.

These additional risk minimisation measures are for the following risk:

Stroke (Cerebrovascular accident)

Prolongation of regadenoson-induced seizures following administration of

aminophylline

Direct healthcare professional communication

Objective and rationale

• A Direct Healthcare Professional Communication (DHPC) to educate the identified risk of cerebrovascular

accident and the risk of aminophylline prolongation of regadenoson-induced seizure and the relevant clinical

actions to minimize these occurrences.

Proposed action - Completed

• Direct HCP communication was implemented 23 Dec 2014

Safety in patients with severe liver disease (hepatic impairment)

A study to examine the safety of Rapiscan in patients with severe liver disease


To assess the safety profile in patients with liver impairment and to observe common adverse events reported in

the post marketing setting.

Proposed action

A study was completed which examined the safety profile of regadenoson in patients with severe liver disease.

Use in combination with exercise

A study to examine the safety of Rapiscan in combination with exercise


• To assess the safety and efficacy of Rapiscan administered in combination with exercise.



Page 39 of 45

Proposed action

• A study was completed which examines the safety and efficacy of regadenoson administered in combination

with exercise.

• The SPC was changed.



Page 40 of 45

VI.2.5 Planned post authorisation development plan

List of studies in post authorisation development plan

Study/activity

(including study

number)

Objectives Safety concerns

/efficacy issue

addressed

Status Planned date for

submission of

(interim and) final

results

3606-CL-3001

A phase 4,

multicenter, double-

blind, randomized,

placebo-controlled

study of the safety and

tolerance of

regadenoson in

subjects with asthma

or chronic obstructive

pulmonary disease

(COPD).

To determine the

safety and tolerability

of regadenoson as

measured by change

in forced expiratory

volume in 1 second

(FEV1) when

administered to

subjects with hyper-

responsive or

obstructive airway

disease (i.e., asthma

or COPD)

In the asthma stratum,

there was no

statistically significant

difference in the

proportion of subjects

with a > 15% decrease

in FEV1 from

baseline to the 2-hour

post baseline

assessment in the

regadenoson group

(1.1%) compared with

the placebo group

(2.9%)

In the COPD stratum,

there was no

statistically significant

difference in the

proportion of subjects

with a >15% decrease

in FEV1 from

baseline to the 2-hour

post baseline

assessment in the

regadenoson group

(4.2%) compared with

the placebo group

(5.4%)

Completed Submitted 2011



Page 41 of 45

Study/activity

(including study

number)


/efficacy issue

addressed


submission of

(interim and) final

results

3606-CL-3010

A phase 4,

multicenter, double-

blind, randomized,

placebo-controlled

study of the safety and

tolerance of

regadenoson in

subjects with renal

impairment

To determine the

safety and tolerability

of regadenoson in

subjects with Stage III

or Stage IV renal

impairment

Regadenoson was safe

and well tolerated in

subjects with Stage III

or Stage IV renal

impairment.

There were no SAEs

that occurred during

the study from the

start of study drug

administration until

follow-up at 24 hours

post dose.


3606-CL-3002

A Phase 3b,

Multicenter,

Randomized, Double-

Blind, Placebo-

Controlled Study to

Evaluate the Effect of

Caffeine Intake on

Single Photon

Emission Computed

Tomography

(SPECT) Myocardial

Perfusion Imaging

(MPI) in Subjects

Administered

Regadenoson.

To determine whether

oral administration of

200 mg or 400 mg

caffeine adversely

compromised

diagnostic accuracy of

detecting reversible

defects in adult

subjects with a known

likelihood of coronary

artery disease (CAD)

undergoing single

photon emission

computed tomography

(SPECT) myocardial

perfusion imaging

(MPI) with

regadenoson

Caffeine adversely

compromised the

diagnostic accuracy of

detecting ischemic

reversible defects in

adult subjects with a

known likelihood of

CAD undergoing

SPECT MPI with

regadenoson.




Page 42 of 45

Study/activity

(including study

number)


/efficacy issue

addressed


submission of

(interim and) final

results

3606-CL-2001

A Phase 2, Open-

Label, Randomized,

Cross-Over Study of

Regadenoson in

Subjects Undergoing

Stress Myocardial

Perfusion Imaging by

Multidetector

Computed

Tomography (MDCT)

and Single Photon

Emission Computed

Tomography

(SPECT)

To establish the non-

inferiority of


imaging (MPI) using

Multidetector

Computed

Tomography (MDCT)

with regadenoson as

compared to Single

Photon Emission

Computed

Tomography (SPECT)

with regadenoson in

detecting the presence

or absence of

ischemia (number of

reversible defects).

To assess the safety

and efficacy of

regadenoson (400

mcg) during the

acquisition of


MDCT vesus SPECT

imaging.

Completed Final study report

submitted Dec 2013.

3606-CL-1005

A Phase 1,

Randomized, Double-

blind, Dose

Escalation, Parallel

Group, Placebo-

controlled, Repeat

Dose Tolerance Study

of Regadenoson in

Healthy Subjects

To determine the

safety, tolerability,

and pharmacokinetics

of two or three repeat

intravenous (IV) bolus

doses of regadenoson

administered 10

minutes apart in

healthy supine

subjects

The safety of repeat

dosing within less

than 24 hours is not

known. This study is

designed to assess the

safety of two or three

repeat doses 10

minutes apart.

Completed Study status noted in

PSUR#7, dated 18 Jun

2014.

Final study report

submitted Jun 2014



Page 43 of 45

Study/activity

(including study

number)


/efficacy issue

addressed


submission of

(interim and) final

results

3606-CL-3004

A Phase 3b, Open-

Label, Parallel Group,

Randomized,

Multicenter Study to

Assess Regadenoson

Administration

Following an

Inadequate Exercise

Stress Test as

Compared to

Regadenoson Alone

For Myocardial

Perfusion Imaging

(MPI) Using Single

Photon Emission

Computed

Tomography

(SPECT).

To demonstrate that

the strength of

agreement between

single photon

emission computed

tomography (SPECT)

imaging with

regadenoson

following inadequate

exercise stress testing

and SPECT imaging

with regadenoson

alone is not inferior to

the strength of

agreement between

two sequential

regadenoson SPECT

images without

exercise

The safety and

efficacy of the

combination of

regadenoson with

exercise.

Completed Post-marketing safety

assessment of

regadenoson in

combination with

exercise (3606- CL-

3004) is completed.

Studies which are a condition of the marketing authorisation

None of the above studies are conditions of the marketing authorisation.

VI.2.6 Summary of changes to the Risk Management Plan over time

Major changes to the Risk Management Plan over time

Version Date Safety Concerns Comment

1.1 At time of

Marketing

Authorization

07/09/2010

Identified Risks:

• SA/AV nodal block

• Myocardial ischemia

• Hypotension

• Dyspnoea

Gilead Sciences

International Ltd (MAH)

at time of Rapiscan

Marketing Authorization.



Page 44 of 45


• Headache

• Interaction with dipyridamole Potential Risks:

• Bronchoconstriction Missing Information

• Safety in children

• Safety in pregnancy

• Safety in lactation

• Safety in patients with hepatic disease

• Safety in patients with renal impairment

• Safety in patients with prolonged QT syndrome

2.0 At time of

authorisation of

Marketing

Authorization

Holder transfer to

RPS EU Ltd

11/01/2011

Details of the PASS study were updated.

Results of the Phase 4 studies investigating the safety

and tolerance of regadenoson in subjects with asthma or

chronic obstructive pulmonary disease (Study 3606-CL-

3001) or renal impairment (Study 3606-CL-3010) were

included.

Safety in patients with renal impairment was removed

from list of missing information.

MAH RPS EU Ltd adopts

RMP of prior MAH

Gilead Sciences and

updates as appropriate.

3.0 July 2011 Dyspnoea and headache were removed as identified

risks.

Results of the Phase 3b study evaluating the effect of

caffeine intake on Single Photon Emission Computed

Tomography (SPECT) Myocardial Perfusion Imaging

(MPI) in subjects administered regadenoson (Study

3606-CL-3002) were included.

4.0 June 2013 Added “hypersensitivity” as an important identified risk

and included “off-label use involving exercise” as an

important potential risk.

Added 3606-CL-3004 to post-authorization

development plan.

RMP updated to new

RMP template according

to 2012 EU PV

legislation.



Page 45 of 45


5.0 December 2013 Added “Seizures”, “worsening/recurrence of atrial

fibrillation” and “elevated blood pressure” as important

identified risks and “CVA” as an important potential

risk

RMP updated to reflect

the current “Guidance on

format of the risk

management plan (RMP)

in the EU – in integrated

format” (25 July 2013,

EMA/465932/2013

Rev.1).

6.0 May 2014 Added “Cerebrovascular accident (CVA)” and

“prolongation of regadenoson induced seizures

following aminophylline” as important identified risks.

Reclassified “elevated blood pressure” to “elevated

blood pressure and hypertensive crisis”.

RMP updated in line with

the PRAC Rapporteur

final report

EMEA/H/C/001176/PSU

012 dated 08 May 2014

7.0 October 2014 Updates regarding the additional risk minimization

measure of a Direct Healthcare Professional

Communication.


the PRAC Rapporteur

preliminary assessment

report

EMEA/H/C/001176/PSU

V/0015 dated 05 Sep

2014-Request for

supplementary

information

8.0 May 2015 Updates to combine respiratory arrest and

bronchoconstriction under a single important identified

risk “Respiratory compromise (bronchoconstriction and

respiratory arrest)”


the PRAC PSUR

assessors report for

PSUR#8

EMEA/H/C/PSUSA/00

002616/201410 dated 07

May 2015

9.0 June 2016 Updates to clinical and post-marketing exposures and

completion of Study 3606-CL-3004.

10.0 May 2017 Updates to reflect the proposed indication of FFR and

completion of PASS 401 study (01-1-401)

The overall safety profile

has not changed.

Documents

Regadenoson (Rapiscan®) : RMP summary€¦ · The RMP summary contains information on the medicine's safety profile and explains the measures that are taken in order to further investigate