Cardiac therapy, other cardiac preparations - ATC code: C01EB21

Regadenoson

Each 5 ml vial contains 400 micrograms regadenoson (80 micrograms/ml). Excipient(s): Each 5 ml vial contains 19.26 mg of sodium.

Solution for injection Clear, colourless solution.

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.

When possible, dipyridamole should be withheld for at least two days prior to Rapiscan administration.

Aminophylline may be used to attenuate severe and/or persistent adverse reactions to 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 the ECG parameters, heart rate and blood pressure have returned to pre-dose levels.

Repeated use

This product is to be administered only once within a 24 hour period. Safety and tolerability of repeated use of this product within 24 hours has not been characterised.

Paediatric population

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

Elderly

No dose adjustment is necessary

Hepatic impairment

No dose adjustment is necessary

Renal impairment

No dose adjustment is necessary

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

No dose adjustment is necessary

• Hypersensitivity to the active substance or to any of the excipients.

• 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. Continuous ECG monitoring should be performed and vital signs should be monitored at frequent intervals until the ECG parameters, heart rate and blood pressure have returned to pre-dose levels.

Rapiscan should be used with caution and should only be administered in a medical facility with cardiac monitoring and resuscitation equipment. Aminophylline may be administered in doses ranging from 50 mg to 250 mg by slow intravenous injection (50 mg to 100 mg over 30-60 seconds) to attenuate severe and/or persistent adverse reactions to Rapiscan.

Myocardial ischaemia

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

Sinoatrial and atrioventricular nodal block

Adenosine receptor agonists including regadenoson can depress the sinoatrial (SA) and AV nodes and may cause first, second or third degree AV block, or sinus bradycardia.

Hypotension

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

Bronchoconstriction

Adenosine receptor agonists may cause bronchoconstriction and respiratory compromise. For patients with known or suspected bronchoconstrictive disease, chronic obstructive pulmonary disease (COPD) or asthma, appropriate bronchodilator therapy and resuscitative measures should be available prior Rapiscan administration.

Long QT syndrome

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

Warnings related to excipients

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

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. 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.

Aminophylline (100 mg, administered by slow intravenous injection over 60 seconds) injected1 minute after 400 micrograms regadenoson in subjects undergoing cardiac catheterisation, was shown to shorten the duration of the coronary blood flow response to regadenoson as measured by pulsedwave Doppler ultrasonography. Aminophylline has been used to attenuate adverse reactions to Rapiscan.

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.

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.

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. Aminophylline may be used to attenuate severe or persistent adverse reactions to Rapiscan.

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.

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.

Adenosine receptor agonists, including Rapiscan, can depress the SA and AV nodes and may cause first, second or third degree AV block, or sinus bradycardia requiring intervention. In clinical trials first degree AV block (PR prolongation > 220 msec) developed in 3% of patients within 2 hours of Rapiscan administration; transient second degree AV block with one dropped beat was observed in one patient receiving Rapiscan. In postmarketing experience, third degree heart block and asystole have been reported within minutes of Rapiscan administration.

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

Regadenoson increases sympathetic tone, which causes an increase in heart rate and a shortening of the QT interval. In a patient with a long QT syndrome, sympathetic stimulation can result in less shortening of the QT interval than is normal and may even cause a paradoxical increase in the QT interval. In these patients, the phenomenon of R-on-T syndrome can occur, wherein an extra beat interrupts the T wave of the previous beat, and this increases the risk of a ventricular tachyarrhythmia.

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

Elderly population

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

Rapidscan Pharma Solutions EU Ltd

(POM)

15 February 2012