Coralan - SPC

PROCORALAN
Contents
0. Data sheet for PROCORALAN............................................................................................... 2

1. Posology and method of administration............................................................................... 6
2. Kinetic characteristics (+ cytochrome P450) ......................................................................... 7
3. Mechanism of action on the If current and heart rate.......................................................... 8
4. Preservation of cardiac electrophysiology and haemodynamics .................................... 11
5. What to do in the event of anaesthesia................................................................................ 13
6. Procedure for cardiovascular investigations ...................................................................... 14
7. Effect on heart rate ................................................................................................................. 16
8. Antianginal and anti-ischaemic efficacy ............................................................................. 18
9. Prevention of cardiovascular events.................................................................................... 20
10. The value of PROCORALAN in heart failure .................................................................... 22
11. PROCORALAN and supraventricular arrhythmias ......................................................... 24
12. The value of PROCORALAN in heart transplant recipients............................................ 25
13. Contraindication in pacemaker patients ............................................................................. 27
14. The absence of rebound effect on withdrawal of treatment ............................................. 28
15. Association with beta-blockers ............................................................................................. 29
16. Pregnancy and breast-feeding .............................................................................................. 31
17. Children ................................................................................................................................... 32
18. The elderly............................................................................................................................... 33
19. Renal impairment ................................................................................................................... 34
20. Hepatic impairment ............................................................................................................... 35
21. Respiratory failure (absence of bronchospasm) ................................................................. 36
22. Diabetic subjects ..................................................................................................................... 37
23. Sportsmen and sportswomen ............................................................................................... 38
24. Clinical and biological acceptability .................................................................................... 39
25. Visual tolerance ...................................................................................................................... 41
26. What to do in the event of an overdose............................................................................... 43
27. Disease what to do if cardiac occurs .................................................................................... 44
28. Association / interactions with common cardiology drugs............................................. 47
29. Association with sildenafil (VIAGRA) ................................................................................ 50
30. Comparison with beta-blockers............................................................................................ 51
DIS-2010 1
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DATA SHEET FOR PROCORALAN
I – PHYSICOCHEMICAL CHARACTERISTICS
- I.N.N. : ivabradine
- Chemical name : 3-(3-{[((7S)-3,4-dimethoxybicyclo[4,2,0]
octa-1,3,5-trien-7-yl)methyl]methylamino}propyl)
-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-
benzazepin-2-one hydrochloride.
- Chemical formula : C 27 H 36 N 2 O 5, HCl
- Molecular weight : 505.1 (468.593 + 36.461)
- Appearance : white to pale yellow powder
- Solubility in water : 47 mg/ml in water
44 mg/ml in 5% glucose solution
14 mg/ml in physiological saline
(0.9%)
- Solubility in organic solvents : soluble in dimethyl sulphoxide (DMSO)
- pKa : 2.4 (amide function)
8.5 (amine function)
- pH : 5.1 (for a 10 mg/ml aqueous solution)
II - TOXICOLOGY
1°) After single-dose administration
- Animal species (male animals) : mouse, rat, dog.

- Routes of administration : I.V., P.O.
- Single-dose toxicity studies
Species Observed max. non-lethal dose Observed min. lethal dose

(mg/kg) (mg/kg)
P.O. Mouse 557 742
Rat (Sprague-Dawley) 557 742
Dog ND ND
(doses tested: 37, 70) (doses tested: 37, 70)
Dog (after dose 11 > 11 and < 22
escalation)
I.V. Mouse 37 56
Rat (Sprague-Dawley) 56 74
Dog 9.3 9.3
- Probable cause of death (rodents, dog): neurobehavioural changes and death;
DIS-2010 2
2°) After repeated administration: 4-, 13-, 26- and 52-week studies conducted in Wistar
rats and Beagle dogs.
- NOAEL doses (mg/kg/day) (no observable adverse effect level)
Studies (duration) 4 weeks 13 weeks 26 weeks 52 weeks

Wistar rat (male) 6.5 7 3 b.i.d. (= 3 x 2) < 3 b.i.d. (= < 3 x 2)
Beagle dog 4.6 3 <2 3.5 b.i.d. ( = 3.5 x 2)
- Toxic effects observed at doses > NOAEL doses:

The entire toxicology programme indicates that, in all the species considered, the
heart is the main organ affected, but that other species-dependent effects occur.
- Effect on the heart:

In rodents, chronic administration of high doses of ivabradine (2 to 10 times the
human dose of 7.5 mg twice daily) caused focal inflammatory lesions to appear
within the myocardium. These foci were associated with degeneration of
myocardial muscle fibres and the development of left ventricular fibrosis.
These modifications occurred in response to excessively high doses and do not
reflect true cardiotoxicity.
These changes, observed in rodents, are not clinically relevant, because in patients
with angina, the initially high heart rate (HR) will be reduced to a normal level,
whereas in the toxicology studies, the animals’ HR were reduced to subnormal
levels and maintained there over extended periods. It is therefore unlikely that
similar lesions would be initiated in patients treated at therapeutic doses.
In dogs, maximum plasma concentrations of ivabradine (20-fold those found in
humans treated with 7.5 mg x 2/day) were sometimes associated with ECG
changes, characterised by sinus bradycardia, sinoatrial (or atriosinus?) block or
arrest, and first or second degree AV block.
- Effect on the visual system:

As visual effects occurred during clinical trials, electroretinography (ERG)
investigations were performed during the 1-year study in dogs.
These examinations showed that the changes recorded in the ERGs particularly
affected the responses involving the cone system, and that these changes were
reversible on withdrawal of the treatment;
Moreover, no histological or ultrastructural changes were reported: these
examinations were performed on sections of the eyes of dogs in which the 24-hour
AUC was 50-fold that of patients treated with 7.5 mg x 2/day.
These effects are due to the cross-affinity that ivabradine can have for retinal Ih
channels, which share high structural homology with the If channels of the sinus
node.
- Effect on other organs:

Few effects have been reported on the other organs and apparently must not be
reported in humans exposed to therapeutic doses.
- In vitro and in vivo genotoxicity:

The results of a battery of in vitro and in vivo genotoxicity tests performed according
to the ICH (International Conference on Harmonisation) guidelines showed no
mutagenic effects or clastogenic activity.
DIS-2010 3
- Carcinogenicity:
No carcinogenicity (rat, mouse).
- Reproductive toxicology:
Ivabradine does not affect the fertility of male or female rats;
In gestating female animals treated at dose levels close to therapeutic doses, a
higher incidence of neonatal and intrauterine deaths was reported, as well as a
higher incidence of foetuses with cardiac malformations in rats, or ectrodactyly in
rabbits.
Animal studies indicate that ivabradine is secreted in milk.
Consequently, ivabradine must not be administered during pregnancy or while
breast-feeding.
- Immunotoxicity:
No immunotoxic potential (rat).
- Phototoxicity:
No photocytotoxic effect (in vitro tests).
III - PHARMACOKINETICS
1°) Assay method for plasma and urine
- Storage conditions : plasma = at least 26 months at –18 °C

urine = at least 12 months at –18 °C
- Assay technique : solid phase extraction followed by

a LC-MS-MS technique.
The compounds assayed are ivabradine and one of its metabolites, the N-demethylated
derivative.
2°) The main pharmacokinetic parameters of ivabradine

Absorption
- Rapid and near complete absorption : 90%
- T max : 1 hour (at steady -state)
- Moderate bioavailability : 40%
Distribution
- Plasma protein binding : 70%
- Volume of distribution, Vss : 100 litres (moderate)
Elimination
- Total clearance, CL (ml/min) : 400 ml/min (high)
- Renal clearance : 20 % of CL (moderate)
- Main elimination half-life, t1/2 (hours) : 2 hours
- Effective elimination half-life, t1/2 : 11 hours
- % excreted in the faeces : 52%
- % excreted in the urine : 45%
The kinetics are linear for both time and dose.

Steady-state is reached within 24 hours.
Inter-individual variability is moderate (30%).
DIS-2010 4
3°) Metabolism
Ivabradine is extensively metabolised, exclusively by the cytochrome CYP3A4;

moreover ivabradine is a weak inhibitor of CYP3A4.
The major metabolic routes involved are dealkylation, hydroxylation and
dehydrogenation reactions.
The major metabolite is the N-demethylated compound.
Ivabradine neither induces nor inhibits other isoenzymes of the
CYP450 family.
4°) Dialysis and activated charcoal
- Dialysability: ivabradine is not removed by dialysis.
- Absorption by activated charcoal: ????
DIS-2010 5
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POSOLOGY AND METHOD OF ADMINISTRATION
The usual recommended starting dose of PROCORALAN is 5 mg twice daily. After 3 to 4 weeks
of treatment, the dose may be increased to 7.5 mg twice daily, depending on the therapeutic
response.
The tablets must be taken orally twice daily, once in the morning and once in the evening,
during meals.
If the heart rate decreases persistently below 50 beats per minute (bpm) at rest or if the patient
exhibits bradycardia-related symptoms (dizziness, fatigue or hypotension, etc.), the dose must
be reduced to 2.5 mg twice daily (i.e. one half-tablet of the 5-mg strength twice daily). Treatment
must be discontinued if the heart rate remains below 50 bpm or if the bradycardia-related
symptoms persist.
Since PROCORALAN has been studied in limited numbers of patients aged 75 years or more, a
lower starting dose should be used (2.5 mg twice daily, i.e. one half-tablet of the 5-mg strength,
twice daily), before increasing the dose if necessary.
Crushing the tablets
PROCORALAN tablets can be dissolved in a glass of water, soft drink or orange juice. However,
administration with or in grapefruit juice is forbidden due to metabolic interaction with
cytochrome P450 (CYP3A4).
The disintegration and dissolution time of the tablet is very short (less than 15 minutes).
PROCORALAN tablets may also be crushed and administered as a suspension: the kinetics of
the release of the active substance from crushed tablets will be relatively unchanged, the
disintegration time of the tablet in an artificial gastric fluid being less than 30 minutes. The
powder can be mixed with a fruit purée, but the use of dairy products is not recommended.
For administration using a gastric tube, it must be prepared using the procedure described
below:
- after crushing in a mortar the number of units to administer, take up the powder in water or
a viscosified solution, then administer orally or by syringe into the gastric tube;
- the preparation must be administered within one hour in order to avoid the risk of
degradation of the active substance, the stability of which cannot be guaranteed once it has
been removed from its packaging.
Similarly, in cases of polypharmacy it is preferable not to mix PROCORALAN powder with a

powder of another medicinal product.
DIS-2010 6
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KINETIC CHARACTERISTICS (+ CYTOCHROME P450)
Under physiological conditions, ivabradine is released rapidly from the tablets and is very
soluble in water. Ivabradine is the S enantiomer and no bioconversion has been demonstrated in
vivo. The major active metabolite of ivabradine is the N-demethylated derivative.
Ivabradine is rapidly and almost completely absorbed after oral administration, and the peak
plasma concentration is reached after one hour. The absolute bioavailability of the tablets is
approximately 40%, due to a first-pass effect in the gut and liver.
Concomitant food intake slows absorption by approximately one hour and increases plasma
exposure by 20 to 30%. Taking tablets during meals is recommended in order to reduce intra-
individual variability to plasma exposure.
The volume of distribution at steady-state is close to 100 litres.

The plasma protein binding of ivabradine is approximately 70%.
The peak plasma concentration following chronic administration at a dose of 5 mg twice daily is
approximately 22 ng/ml. The average plasma concentration at steady-state is 10 ng/ml.
Ivabradine is extensively metabolised in the gut and liver by an oxidative process involving
cytochrome P450 3A4 (CYP3A4).
The plasma concentrations of the N-demethylated derivative represent approximately 40% of
those of the parent molecule. This derivative is also metabolised by CYP3A4.
However, ivabradine is a very weak inhibitor of CYP3A4 and therefore does not affect the
metabolism or plasma concentrations of other CYP3A4 substrates, whether they are weak,
moderate or potent inhibitors.
However, drug interaction studies have shown that CYP3A4 inhibitors increase the plasma
concentrations of ivabradine and CYP3A4 inducers reduce them.
Ivabradine is eliminated with a main plasma half-life of 2 hours and an effective half-life of
11 hours. The total clearance is 400 ml/min and renal clearance 70 ml/min. The metabolites are
excreted in equivalent quantities in the faeces and urine. Four percent (4%) of an oral dose is
excreted unchanged in the urine.
No pharmacokinetic differences have been observed between elderly patients and the general
population.
Renal impairment has little impact on the pharmacokinetics of ivabradine, given that renal
clearance accounts for only a small proportion (approximately 20%) of the total elimination of
ivabradine and its metabolite. No data are available on patients with severe renal impairment.
Ivabradine and its metabolite are not removed by dialysis.
In patients with mild hepatic impairment, the concentrations of ivabradine and its active
metabolite are approximately 20% higher than those in patients with normal hepatic function.
However there are insufficient data available to draw conclusions about dose adjustment in
patients with mild to moderate hepatic impairment. No data are available on patients with
severe hepatic impairment.
DIS-2010 7
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MECHANISM OF ACTION ON THE If CURRENT AND HEART RATE
1) The HCN channels
The channels responsible for the If current are called HCN (Hyperpolarisation-activated Cyclic
Nucleotide-gated) channels. Four distinct isoforms (HCN1-4) have been identified, and the
genes encoding these isoforms have been cloned (BIEL, KAUPP). The various isoforms of the
HCN channels differ in their electrophysiological properties and in their tissue distribution
(heart, brain and retina).
HCN4 is the predominant isoform in the sinus node of mice, rabbits and humans, whereas
HCN1 and HCN2 are expressed in much lower quantities in this tissue (SHI, MOOSMANG,
THOLLON).
The HCN1 isoform is highly expressed in the brain, whereas the HCN2 isoform is found in both
the brain and heart. HCN1 is also the predominant isoform in retinal structures and generates a
current resembling the cardiac If current, termed the Ih current (CERVETTO).
The If current or main "pace-maker" current of the heart is a predominantly inward Na+/K+
current activated by membrane hyperpolarisation. It is responsible for the slope of slow diastolic
depolarisation of the action potential (DIFRANCESCO, BABUTY, COUETTE). Inhibition of this
If current increases the interval between adjacent action potentials, resulting in a decrease in the
heart rate.
The presence of ventricular If channels, i.e. a tissue site other than the sinus node, have been
demonstrated, but in the dog and guinea-pig (YU, MICHELS). These channels are only activated
at potentials 50 to 100 mV lower than the activation potentials of the sinus node If current, which
in principle excludes any physiological role.
It has only been possible to describe a functional (physiological) role for these channels and the
associated currents in the sinus node.
Encl.
YU H., CHANG F., COHEN I.S.

Pacemaker current exists in ventricular myocytes.
Circulation Res. 1993 ; 72 : 232-236
YU H., CHANG F., COHEN I.S.

Pacemaker current If in adult canine cardiac ventricular myocytes.
J. Physiol. 1995 ; 485 (2) : 469-483
BOIS P., BESCOND J., RENAUDON B., LENFANT J.

Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial
node cells.
Br. J. Pharmacol. 1996 ; 118 : 1051-1057
SHI W., WYMORE R., YU H. et al.

Distribution and prevalence of hyper-polarization-actived cation channel (HCN) mRNA
expression in cardiac tissues.
Circ. Res. 1999 ; 85 : e1-e6.
DIS-2010 8
KAUPP U.B., SEIFERT R.
Molecular diversity of pacemaker ion channels.
Annu. Rev. Physiol. 2001 ; 63 : 235-257.
MOOSMANG S., STIEBER J., ZONG X., et al.

Cellular expression and functional characterization of four hyper-polarization-actived
pacemaker channels in cardiac and neuronal tissues.
Eur. J. Biochem. 2001 ; 268 : 1646-1652.
BABUTY D., ARGIBAY J.

Electrophysiologie cardiaque.
Encycl. Med. Chir. 2001.
BIEL M., SCHNEIDER A., WAHL C.

Cardiac HCN channels : structure, function and modulation.
Trends in Cardiovascular Medicine 2002 ; 12 : 206-212.
DIFRANCESCO D.
If inhibition: a novel mechanism of action.
Eur. Heart J. 2003 ; 5 (suppl.G) : G19-G25
MICHELS G., FIKRET E., KHAN I., et al.

Single-channel properties support a potential contribution of hyperpolarization-activated cyclic
nucleotide-gated channels and If to cardiac arrhythmias.
Circulation 2005 ; 111 : 399-404
COUETTE B., MARGER L., NARGEOT J., MANGONI M.E.

Physiological and pharmacological insights into the role of ionic channels in cardiac pacemaker
activity.
Cardiovasc. Haematological Disorders-Drug Targets 2006 ; 6 :169-190.
THOLLON C., BEDUT S., VILLENEUVE N. et al.

Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in
pacemaker activity.
Br. J. Pharmacol. 2007 ; 150 : 37-46.
CERVETTO L., DEMONTIS G.C., GARGINI C., et al.

Cellular mechanisms underlying the pharmacological induction of phosphenes.
Br. J. Pharmacol. 2007 ; 150 : 383-390.
2) Inhibition of the I f current by ivabradine
PROCORALAN is the first selective and specific inhibitor of the sinus node If current approved
for clinical use.
PROCORALAN has a pure heart rate lowering effect, by acting on the sinus node. More
precisely, PROCORALAN binds selectively and specifically to the sinus node If channels. These
channels are the source of the If current which is the major determinant of the heart’s pacemaker
activity. Indeed, the If current modulates the slope of the slow diastolic depolarisation of the
sinus node cells on which the heart rate depends (DIFRANCESCO).
By selectively inhibiting the If current, PROCORALAN reduces the slope of slow diastolic
depolarisation, which results in a decrease in the frequency of the action potentials and therefore
a decrease in heart rate.
DIS-2010 9
The If current is a predominantly inward Na+ K+ current, activated by membrane
hyperpolarisation. PROCORALAN acts directly on the If channels of the "pacemaker" cells of the
heart, by entering the channel pore from the intracellular side. It binds to a specific site and then
blocks the inward ionic flow (BUCCHI).
The novelty of ivabradine results from its specific binding to its site present in the If channel: it
acts directly, unlike other compounds that ultimately act on this channel via ubiquitous
intracellular molecules such as cAMP. In vivo studies show that ivabradine specifically blocks
the If channels, with binding only occurring when the channel is open. Blockade is therefore
dependent on If channel activation; the number of channels blocked depends on the plasma
concentration of ivabradine.
In the clinical setting, the higher the resting heart rate, the more marked the heart rate reduction
induced by PROCORALAN, which therefore limits the risk of bradycardia in patients with a
lower resting heart rate.
Heart rate reduction is also dose-dependent, with a plateau effect at high ivabradine
concentrations. When all the If channels are blocked experimentally, the heart rate reduction
obtained with PROCORALAN does not exceed 35%.
In fact, in clinical studies, the mean heart rate reductions observed range from 10 to 15 bpm,
both at rest and during exercise.
In contrast to zatebradine, the development of which has been suspended, PROCORALAN

selectively inhibits the sinus node If current at concentrations that have no effect on other
currents, in particular the T- and L-type calcium currents and the delayed rectifier potassium
current (BOIS); it does not prolong the action potential duration.
Encl.
BOIS P., BESCOND J., RENAUDON B., LENFANT J.

Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial
node cells.
Br. J. Pharmacol. 1996 ; 118 : 1051-1057
BABUTY D., ARGIBAY J.

Electrophysiologie cardiaque.
Encycl. Med. Chir. 2001.
BUCCHI A., BARUSCOTTI M., DIFRANCESCO D.

Current-dependent block of rabbit sino-atrial node If channels by ivabradine.
J. Gen. Physiol. 2002 ; 120 : 1-13.
DIFRANCESCO D.
If inhibition: a novel mechanism of action.
Eur. Heart J. 2003 ; 5 (suppl.G) : G19-G25
DIFRANCESCO D., CAMM J.A.

Heart rate lowering by specific and selective If current inhibition with ivabradine
Drugs 2004 ; 64 (16) : 1757-1765
COUETTE B., MARGER L., NARGEOT J., MANGONI M.E.

Physiological and pharmacological insights into the role of ionic channels in cardiac pacemaker
activity.
Cardiovasc. Haematological Disorders-Drug Targets 2006 ; 6 :169-190.
DIS-2010 10
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PRESERVATION OF CARDIAC ELECTROPHYSIOLOGY

AND HAEMODYNAMICS
1) Preservation of cardiac electrophysiology
Ivabradine, the active substance in PROCORALAN, does not alter intra-atrial, atrioventricular
or intraventricular conduction.
In particular, ivabradine administration has no effect on the PR or QRS intervals, atrial

conduction or refractory periods, the atrioventricular node, the His-Purkinje system or the
ventricles (CAMM).
By reducing the heart rate, PROCORALAN prolongs the QT interval. Compared to baseline,
intravenous administration of ivabradine at a dose of 0.2 mg/kg prolongs the mean QT interval
by 28.6 ms after 30 minutes and by 37.5 ms after 1 hour (p < 0.001).
However, the QTc interval, corrected for variations in heart rate, is unchanged. Ventricular
repolarisation is therefore preserved with PROCORALAN (CAMM).
2) Preservation of myocardial contractility
PROCORALAN has no negative inotropic effect and the contractile force of the heart is therefore
preserved.
Since PROCORALAN is a pure heart rate lowering agent, it not only reduces the myocardium’s
requirement for oxygen and substrates, but also increases myocardial oxygen supply.
As it has no negative inotropic effect, PROCORALAN increases the duration of effective

diastolic more than a beta-blocker, both at rest and during exercise (COLIN, BERDEAUX).
Indeed, due to their negative inotropic effect, beta-blockers prolong systolic ejection at the
expense of diastole.
Furthermore, PROCORALAN has no negative lusitropic effect at rest and during exercise,
thereby enabling better ventricular myocardial relaxation and therefore greater perfusion of the
subendocardial layers of the myocardium, which are most sensitive to ischaemia (COLIN).
Finally, PROCORALAN preserves coronary vasodilation during exercise at the time when the
myocardium is most exposed to ischaemia (SIMON): unlike propranolol, it does not prevent the
increase in coronary blood flow velocity or the decrease coronary resistance. Enhanced coronary
blood flow during exercise is therefore preserved.
In conclusion, PROCORALAN exclusively reduces the heart rate, both at rest and during
exercise, while also preserving contractility, atrioventricular conduction and ventricular
repolarisation.
3) Preservation of blood pressure and peripheral resistance
PROCORALAN has no effect on smooth muscle fibres and therefore does not alter blood
pressure or cause arterial hypotension.
Using all the blood pressure data collected in the clinical studies, PROCORALAN caused a
clinically insignificant reduction of 1 mmHg (BORER, TARDIF).
DIS-2010 11
Encl.
SIMON L., GHALEH B., PUYBASSET L., et al.

Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and
exercising conscious dogs.
J. Pharmacol. Exp. Ther. 1995 ; 275 (2) : 659-666.
MONNET X., GHALEH B., COLIN P., et al.

Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and
stunning.
J. Pharmacol. Exp. Ther. 2001 ; 299 : 1133-1139
COLIN P., GHALEH B., HITTINGER L., et al.

Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during
exercise.
Am. J. Physiol. Heart Circ. Physiol. 2002 : 282 : H672-679
CAMM A.J, LAU C.P.

Electrophysiological effects of a single intravenous administration of ivabradine (S16257) in
adult patients with normal baseline electrophysiology.
Drugs R&D 2003 ; 4 (2) : 83-89.
COLIN P., GHALEH B., MONNET X.

Contributions of heart rate and contractility to myocardial oxygen balance during exercise.
Am. J. Physiol. Heart Circ. Physiol. 2003 ; 284 : H676-H682.
BORER J.S., FOX K., JAILLON P.

Anti-anginal and anti-ischemic effects of ivabradine, an If inhibitor, in stable angina.
Circulation 2003 ; 107 : 817-823.
COLIN P., GHALEH B., MONNET X., et al.

Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and
diastolic time in exercising dogs.
BERDEAUX A., COLIN P., MONNET X., GHALEH B.

Fréquence cardiaque et ischémie myocardique expérimentale.
Thérapie 2004 ; 59 (5) : 507-510.
MONNET X., COLIN P., GHALEH B., et al.

Heart rate reduction during exercise-induced myocardial ischaemia and stunning.
Eur. Heart J. 2004 ; 25 : 579-586.
TARDIF J.C., FORD I., TENDERA M., BOURASSA M.G., FOX K for the INITIATIVE
Investigators.
Efficacy of ivabradine, a new selective If inhibitor, compared with atenolol in patients with
chronic stable angina.
Eur. Heart J. 2005 ; 26 : 2529-2536
LUCATS L., GHALEH B., COLIN P., et al.

Heart rate reduction by inhibition of If or by β-blockade has different effects on postsystolic wall
thickening.
Br. J. Pharmacol. 2007 ; 150 : 335-341.
DIS-2010 12
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WHAT TO DO IN THE EVENT OF ANAESTHESIA
No specific studies have been conducted in patients treated with PROCORALAN who require
general anaesthesia.
Nevertheless, during the phase III clinical studies, some patients underwent surgery and no
unexpected effects were reported. No interaction was observed between ivabradine and
anaesthetics.
Irrespective of the duration of the operation and the general anaesthesia, PROCORALAN
treatment can be maintained until surgery. Unlike beta-blockers, gradual withdrawal of
PROCORALAN is not necessary, because there is no rebound effect associated with sudden
discontinuation of the treatment.
PROCORALAN treatment can be reintroduced at the same time as food, on condition that the
resting heart rate is greater than or equal to 60 bpm. Some precautions must be observed when
PROCORALAN treatment is reintroduced. Indeed, a low heart rate may be well tolerated
preoperatively but not postoperatively if the operation has resulted in anaemia or
hypovolaemia: a lower dose of PROCORALAN may be used temporarily.
Parenteral anti-ischaemic treatments are recommended during a long operation, where the heart
rate increases intraoperatively or postoperatively to a level capable of causing an episode of
myocardial ischaemia.
For patients requiring emergency surgery whose heart rate is incompatible with anaesthesia, or
in cases of excessive bradycardia that is poorly tolerated from the haemodynamic point of view
(< 40 bpm), the administration of sympathomimetic agents such as isoprenaline or dobutamine,
or even electrical cardiac pacing (pacemaker) can be proposed.
DIS-2010 13
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PROCEDURE FOR CARDIOVASCULAR INVESTIGATIONS
1) Performing a coronary artery CT scan
Due to its properties, PROCORALAN is of potential value when performing a coronary artery
CT scan. It is indeed true, that the slower the heart rate, the easier it is to interpret the image.
Indeed, PROCORALAN’s antianginal mode of action is based on the fact that it is a pure heart
rate lowering agent that does not decrease myocardial contractility or prolong the
atrioventricular conduction or ventricular repolarisation times.
Studies carried out in patients admitted for a coronary artery CT scan show that administering
PROCORALAN by oral route is an effective alternative to betablockers, in terms of reducing the
heart rate and improving image quality (PEREZ DE ISLA, MORENO).
The value of PROCORALAN for injection, for the purposes of performing this examination, is
currently being assessed in 330 patients with a resting heart rate of at least 70 bpm, and who are
not eligible for intravenous betablocker treatment (multicenter study – 20 countries).
2) Performing dobutamine stress echocardiography
Treatment with beta-blockers must be discontinued before performing dobutamine stress

echocardiography, particularly if the purpose of this examination is to detect ischaemia.
Indeed, the expected heart rate acceleration induced by dobutamine is insufficient during
treatment with beta-blockers, rendering the examination rather uninformative.
Only preliminary data about PROCORALAN are available at present.
If channel inhibitors, ivabradine in particular, limit the expected increase in heart rate induced
by the administration of dobutamine (RICHARD).
It is therefore preferable to discontinue PROCORALAN treatment before performing

dobutamine stress echocardiography. Unlike beta-blockers, there is no rebound effect associated
with sudden discontinuation of PROCORALAN treatment; gradual withdrawal is therefore not
necessary.
The main elimination half-life of PROCORALAN in plasma is 2 hours and its effective half-life is
11 hours. As complete elimination of the medicinal product is classically obtained after 5 times
the plasma elimination half-life, PROCORALAN treatment must be stopped at least 48 hours
before the examination.
3) Performing an exercise test (ETT)
As for any antiangina and anti-ischemic treatment, the decision whether PROCORALAN should
or should not be stopped before an exercise test is carried out depends on the purpose of the
examination.
If the aim is to confirm the efficacy of PROCORALAN, then the treatment should be continued;
whereas if it is intended to check whether the coronary artery disease has deteriorated, it may be
necessary to stop the treatment.
DIS-2010 14
In this situation, in contrast to the betablockers, the sudden discontinuation of PROCORALAN
does not induce a rebound effect; dose tapering is not therefore necessary. PROCORALAN is
eliminated with a principal plasma half-life of 2 hours, and an effective half-life of 11 hours.
Thus, treatment with PROCORALAN must be stopped 48 hours before the test is performed.
Encl.
RICHARD V., MULLER E., DERUMEAUX G., MULDER J.P., THUILLEZ C.

Beneficial effects of selective reduction in heart rate in a rat model of cardiac stunning.
Interactions with dobutamine.
Congrès annuel de la Société Française de Pharmacologie, 2002, abstract A347
DIFRANCESCO D., CAMM J.A.

Heart rate lowering by specific and selective If current inhibition with ivabradine
Drugs 2004 ; 64 (16) : 1757-1765
PEREZ DE ISLA L., ZAMORANO J., PIZARRO G. et al.

Oral ivabradine : an alternative to endovenous beta-blockade in the context of CT coronary
angiography (CTCA). Heart rate reduction, image quality and motion artifacts.
Eur. Heart J. 2009; 30 (suppl.): abstract P3039
MORENO P., ZAMORANO J.L., SANCHEZ T. et al.

Ivabradine stabilizes sinus heart rhythm and boost quality scan: comparison with oral and
intravenous betablockers.
Eur. Heart J. 2009; 30 (suppl.): abstract P4563
DIS-2010 15
-7-
EFFECT ON HEART RATE
By selectively inhibiting the sinus If current, PROCORALAN reduces the slope of the slow
diastolic depolarization of the action potential, which leads to a reduction in the frequency of the
action potentials, and therefore to a reduction in the heart rate.
During clinical studies, the mean reduction in heart rate observed with PROCORALAN is
between 10 and 15 beats per minute (bpm), both at rest and during exercise.
The slowing of the heart rate induced by PROCORALAN is therefore greater the higher the
initial heart rate, which limits the risk of bradycardia in patients with the lowest resting heart
rates (LE HEUZEY).
The binding and displacement of ivabradine from its site inside the f channel occurs only when
the channel is open. Blockade of the channel therefore depends on its activation, which helps to
contribute to increase the inhibition produced at high heart rates.
The slowing of the heart rate produced by PROCORALAN is also dose-dependent with a
plateau effect at high concentrations of ivabradine (LE HEUZEY). The lowering of the heart rate
by PROCORALAN does not exceed 35% when all the If channels are experimentally blocked.
A dose-effect study carried out in 360 patients with stable coronary artery disease, randomly
assigned under double blind to 4 parallel groups, the effects of ivabradine administered at doses
of 2.5 mg, 5 mg and 10 mg twice a day for two weeks was compared to those of a placebo
(BORER). The mean basal heart rate was 69.7 ± 10.3 bpm, ranging from 47 to 106 bpm.
After two weeks of treatment, a significant, dose-related slowing of the heart rate was observed,
reaching 18.7 bpm at rest and 17.7 bpm at the peak level of exercise at the highest dose of
PROCORALAN.
The INITIATIVE (INternatIonal TrIAl on the Treatment of angina with IVabradinE versus
atenolol) study compared the anti-ischemic and anti-angina effects of PROCORALAN to those
of atenolol, in 939 patients presenting with stable angina and followed-up for 4 months
(TARDIF).
The patients were randomly assigned to three groups, two of them receiving ivabradine at a
dose of 5 mg twice daily, and the third 50 mg of atenolol once a day for 1 month.
The doses were then increased to 7.5 mg and 10 mg ivabradine respectively twice a day in the
two ivabradine-treated groups and to 100 mg of atenolol once a day in the third group, for the
next 3 months.
After the study, the heart rates had decreased in all the groups, both at rest and during exercise.
The ASSOCIATE study assessed the anti-ischemic efficacy of PROCORALAN versus placebo in
889 patients with stable coronary artery disease who were already receiving treatment with 50
mg of atenolol (TARDIF).
When included, the patients (mean age = 60 years) had a mean resting heart rate of 67 bpm and
displayed a positive exercise test (unmodified Bruce protocol), despite taking betablocker
treatment.
These patients received for 4 months, in addition to 50 mg atenolol, either ivabradine
(5 mg x 2/day for two months, and then depending on the heart rate, 7.5 mg x 2/day for the
other two months), or a placebo. 87.5% of the patients switched to the dose of
7.5 mg of PROCORALAN twice daily.
After 4 months of treatment, PROCORALAN had induced a further reduction in the resting
heart rate of 8.7 bpm, and in the heart rate at the peak level of exercise of 11.3 bpm.
DIS-2010 16
Finally, the slowing of the heart rate induced by PROCORALAN is maintained long term, with a
statistically significant reduction at rest of 9.7 bpm at the 5-mg dose, and of 12.3 bpm at the dose
of 7.5 mg after one year of treatment. The maximum reduction is obtained within the first month
of treatment and continues up to 12 months (LOPEZ-BESCOS).
Encl.

Circulation 2003 ; 107 : 817-823
TARDIF J.C., FORD I., TENDERA M., BOURASSA M.G., FOX K. for the INITIATIVE
Investigators.
Eur. Heart J. 2005 ; 26 : 2529-2536
LOPEZ-BESCOS L., FILIPOVA S., MARTOS R.

Long term safety and efficacy of ivabradine in patients with chronic stable angina.
Cardiology 2007; 108 : 387-396
BORER J.S., LE HEUZEY J.Y.

Characterization of the heart rate-lowering action of ivabradine, a selective If current inhibitor.
American Journal of Therapeutics 2008; 15: 461-473
TARDIF J.C., PONIKOWSKI P., KAHAN T. for the ASSOCIATE study investigators.
Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving
beta-blocker therapy : a 4 month, randomized, placebo-controlled trial.
European Heart Journal 2009 ; 30 : 540-548.
DIS-2010 17
-8-
ANTIANGINAL AND ANTI-ISCHAEMIC EFFICACY
The antianginal and anti-ischaemic action of PROCORALAN is based primarily on specific heart
rate reduction.
PROCORALAN is the first selective and specific inhibitor of the sinus-node If current, the heart's
main current pacemaker, which leads solely to slowing of the heart rate and spares the other
cardiac parameters (no negative inotropic or dromotropic effects, or lusitropic effects). Slowing
the heart rate with PROCORALAN reduces cardiac work and the oxygen consumption of the
myocardium, and increases the oxygen supply of the myocardium.
PROCORALAN significantly improves all the ergonometric parameters measured during

exercise tests (total exercise duration, time to limiting angina, time to angina onset, and time to
1-mm ST-segment depression), and reduced the number of angina attacks. These efficacy
findings were consistent in all the studies.
After one month of treatment at a dose of 5 mg twice daily, PROCORALAN had improved the
total exercise duration by 64 seconds, and the time to 1-mm ST-segment depression by
69 seconds, at the end of the dose. After nearly three months of supplementary treatment at a
dosage of 7.5 mg twice daily, PROCORALAN had improved the total exercise duration by
86 seconds, and the time to a 1-mm ST-segment depression by 98 seconds, at the end of the dose.
PROCORALAN had reduced the frequency of angina attacks by about 70%.
PROCORALAN is at least as effective as atenolol, the reference drug for the treatment of stable
angina (INITIATIVE).
This study has also provided evidence that for a given reduction in the heart rate,
PROCORALAN is more anti-ischemic than atenolol, whereas it has no negative inotropic effect.
In fact, the increase in the exercise capacity for an equivalent reduction in heart rate is greater
with PROCORALAN than with atenolol. For the same reduction of heart rate by 1 beat,
PROCORALAN increased the total duration of the exercise by 10.1 seconds, where atenolol only
increased it by 5.6 seconds (LE HEUZEY). This is explained by the fact that PROCORALAN
reduces the myocardial oxygen needs, but also allows a definite increase in the oxygen supply to
the myocardium.
The antianginal and anti-ischaemic efficacy of PROCORALAN is maintained long-term

(LOPEZ-BESCOS). After one year of treatment, the slowing of the heart rate induced by
PROCORALAN is associated with a 50% reduction in the number of angina attacks and in short-
acting nitrates consumption.
PROCORALAN given on top of atenolol 50 mg o.d. showed additional efficacy on all ETT
parameters at the trough of drug activity (12 hours after oral intake) (ASSOCIATE).
When included, the patients (n=889) had a mean resting heart rate of 67 bpm, and a positive
exercise test (standard Bruce protocol), despite the betablocker treatment.
For 4 months, the patients received 50 mg of atenolol, plus either ivabradine
(5 mg x 2/day for two months, and then, depending on the heart rate, 7.5 mg x 2/day for the
other two months), or a placebo.
87.5% of the patients switched to the 7.5 mg dose of PROCORALAN twice daily.
The exercise test parameters evaluated at the end of the dose were the total exercise duration
(main criterion), and the time to angina onset, the time to limiting angina, and the time to 1-mm
ST-segment depression.
After 4 months, the addition of PROCORALAN had reduced the resting heart rate by a mean of
9 bpm, and produced a highly significant improvement (p < 0.001) in all the ergonometric
parameters, evaluated at the trough of the drug's activity (12 hours after the previous dose).
DIS-2010 18
A recent sub-group analysis has shown that PROCORALAN significantly improved the exercise
capacity of the patients with coronary artery disease who were already receiving treatment with
50 mg of atenolol, regardless of the initial heart rate (TARDIF).
The patients from the ASSOCIATE study were divided into 2 groups, depending on the median
of the resting heart rate: one group with a resting heart rate that was less than or equal to 65
bpm when included (n=440), and a second group with a resting heart rate of more than 65 bpm
when included (n=420).
After 4 months of treatment, the addition of PROCORALAN reduced the heart rate during
exercise by 10.2 bpm in the first group, and by 12.8 bpm in the second group, and produced a
significant improvement in all the exercise test parameters in both groups.
Finally, the anti-angina efficacy of PROCORALAN is demonstrated regardless of the category of

stable coronary-artery disease patient concerned: elderly patients, diabetics, women, patients
with asthma, chronic bronchitis, arteritis, patients with a history of myocardial infarction,
patients who have undergone revascularization, patients suffering from a cerebrovascular
disorder, independently of the severity of the angina (TENDERA).
Encl.

Circulation 2003 ; 107 : 817-823
RUZYLLO W., TENDERA M., FORD I., FOX K.

Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable
effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial.
Drugs 2007; 67 (3): 393-405
Investigators.
Eur. Heart J. 2005 ; 26 : 2529-2536

Long term safety and efficacy of ivabradine in patients with chronic stable angina.
Cardiology 2007; 108 : 387-396

TARDIF J.C.
Ivabradine improves exercise capacity in patients with stable angina pectoris receiving β-
blockers irrespective of the baseline HR: a subgroup analysis of the randomized controlled
ASSOCIATE study.
Abstract
TENDERA M., BORER J.S., TARDIF J.C.

Efficacy of If inhibition with ivabradine in different subpopulations with stable angina pectoris.
Cardiology 2009; 114: 116-125
DIS-2010 19
-9-
PREVENTION OF CARDIOVASCULAR EVENTS
The BEAUTIFUL (morBidity-mortality EvAlUation of The If inhibitor ivabradine in patients with

CAD and left ventricULar dysfunction) study assessed the benefits of PROCORALAN for the
prevention of cardiovascular events in 10,917 stable coronary artery disease patients with left
systolic dysfunction. The patients were already receiving the best treatment recommended for
coronary artery disease, including betablockers in 87% of cases. They were randomly assigned to
two treatment groups: PROCORALAN and placebo.
The initial dosage of ivabradine was 5 mg twice daily for two weeks; this was then increased to
7.5 mg twice daily if the resting heart rate was still above 60 bpm. The mean duration of
treatment was 19 months.
An analysis of the results in patients with a resting heart rate of > 70 bpm was pre-specified
before the blind was lifted.
The BEAUTIFUL study shows that, on the one hand, a resting heart rate of over 70 bpm
significantly increased the risk of hospitalization with myocardial infarction by 46% (p=0.0066)
and that of revascularization by 38% (p=0.037).
On the other hand, this study has also shown for the first time, that lowering the heart rate alone
with PROCORALAN produces a significant reduction in the risk of coronary events [36%
reduction in myocardial infarctions (p=0.001) and a 30% reduction in revascularizations
(p=0.016)] in stable coronary artery disease patients with a resting heart rate of at least 70 bpm.
In this study, 1507 patients presented with limiting angina when included (734 patients in the
ivabradine group and 773 patients in the placebo group), and were already receiving
betablocker treatment in 90% of cases.
The post-hoc analysis of this sub-group demonstrated, after a median follow-up of 18 months,
that in the patients who still had angina, PROCORALAN produced a significant reduction of
24% in the incidence of major cardiovascular events, including both cardiovascular mortality
and hospital admissions for myocardial infarction or heart failure (p = 0.05). In particular,
PROCORALAN reduced the risk of myocardial infarction (whether fatal or not) by 42% (p =
0.021). The benefit produced by PROCORALAN was still more marked in angina patients with a
resting heart rate equal to or greater than 70 bpm, with a 73% reduction in the risk of myocardial
infarction (whether fatal or not) (p = 0.002).
PROCORALAN is thus the first antiangina drug to demonstrate a reduction in the risk of
myocardial infarction in angina patients, whether they were receiving a betablocker or not.
In conclusion, PROCORALAN improved the cardiovascular prognosis of symptomatic patients

with stable coronary artery disease on condition that their resting heart rate was equal to or
greater than 60 bpm. PROCORALAN protects asymptomatic coronary patients against the risk
of myocardial infarction, on condition that the resting heart rate is equal to or greater than 70
bpm.
Encl.
REIL J-Ch., BOHM M.

BEAUTIFUL results –the slower, the better ?
Lancet 2008 ; 372 : 779-780.
DIS-2010 20
FOX K., FORD I., STEG P.G., et al.
Ivabradine for patients with stable coronary artery disease and left-ventricular systolic
dysfunction (BEAUTIFUL) : a randomised, double-blind, placebo-controlled trial.
Lancet 2008 ; 372 : 807-816.

Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular
systolic dysfunction (BEAUTIFUL) : a subgroup analysis of a randomised controlled trial.
Lancet 2008 ; 372 : 817-821.

Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable
coronary artery disease and left ventricular systolic dysfunction with limiting angina : a
subgroup analysis of the randomized, controlled BEAUTIFUL trial.
European Heart Journal Advance Access published August 31, 2009.
DIS-2010 21
-10-
THE VALUE OF PROCORALAN IN HEART FAILURE
PROCORALAN is the first selective and specific inhibitor of the sinus node If current that exerts
anti-ischemic and antianginal effects by pure heart rate reduction, without altering other
parameters of cardiac function, and in particular without having a negative inotropic effect.
Various experimental studies have shown that cardiac output is maintained during
PROCORALAN treatment, in spite of the reduced heart rate (MANZ, JONDEAU, MULDER,
SIMON). Indeed, since PROCORALAN has no negative inotropic or lusitropic effect, it increases
the stroke volume. In addition, PROCORALAN does not affect blood pressure or peripheral
vascular resistance.
The results of a study carried out in patients with severe heart failure (NYHA stages III or IV –
EF<35%) demonstrate that PROCORALAN, associated with conventional treatment,
significantly reduced the heart rate, was well tolerated and improved the patients' left
ventricular function (JONDEAU).
In a second study carried out in 10 patients with severe heart failure (NYHA stage III – mean
EF = 21%) who were already receiving the recommended treatment, the intravenous
administration of ivabradine (0.1 mg/kg for 90 minutes, 0.05 - 0.075 mg/kg over the next
90 minutes) was well tolerated, significantly reduced the heart rate by more than 20%, increased
the stroke volume, and maintained cardiac output (DE FERRARI).
These encouraging preliminary results have led to the continued development of

PROCORALAN in heart failure.
THE SHIFT study (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) is an
international, multicentre, phase III, randomised, double-blind, placebo-controlled study
(37 countries – 700 centers) conducted in 6,500 patients with moderate to severe chronic heart
failure (CHF), of ischemic or non-ischemic origin, with left ventricular dysfunction (LVD), in
order to observe the effects of ivabradine on cardiovascular events.
The characteristics of the recruited population were:

- men or women over the age of 18 years,
- symptomatic CHF (CHF of all aetiologies except for congenital cardiac disease, severe aortic
or mitral stenosis, severe aortic regurgitation or severe primary mitral regurgitation) NYHA
class II to IV for at least 4 weeks,
- clinically stable for at least 4 weeks, and a prior hospitalization for worsening heart failure
within the previous 12 months,
- optimal CHF treatment, unchanged for at least 4 weeks,
- sinus rhythm with resting HR (by ECG) ≥ 70 bpm,
- LV systolic dysfunction: EF ≤ 35%.
At enrolment, the initial dose of PROCORALAN is 5 mg twice daily with dose adjustment after
two weeks, involving a decrease to 2.5 mg, maintenance at 5 mg or an increase to 7.5 mg twice
daily, depending on heart rate and tolerability. The patients also continue taking conventional
treatment for heart failure. The randomized treatment period will last approximately
12-48 months.
The primary endpoint is the composite of the first event of cardiovascular death or
hospitalization for worsening heart failure.
The first secondary endpoint is the composite of the first event of cardiovascular death or
hospitalization for worsening heart failure in patients receiving at least 50% of the target daily
dose of beta-blockers at randomization.
DIS-2010 22
The other secondary endpoints are:
- all-cause death,
- any cardiovascular death,
- hospitalization for worsening heart failure,
- all-cause hospitalization,
- any cardiovascular hospitalization,
- death from heart failure,
- the composite of cardiovascular death, hospitalization for worsening heart failure, or
hospitalization for non-fatal myocardial infarction,
- changes in functional capacity, assessed by NYHA classification, and changes in the clinical
symptoms of heart failure, assessed by patient and investigator global assessment
questionnaires.
The study is currently underway and the results are expected in 2010.
However, at present, in the absence of sufficient clinical data, the administration of

PROCORALAN is contraindicated in NYHA III-IV class heart failure.
Encl.
SIMON L., GHALEH B., PUYBASSET L., GIUDICELLI J.F., BERDEAUX A.

J. Pharmacol. Exper. Therap. 1995 ; 275 (2) : 659-666.
MANZ M., REUTER M., LAUCK G., OMRAN H., JUNG W.

A single intravenous dose of ivabradine, a novel if inhibitor, lowers heart rate but does not
depress left ventricular function in patients with left ventricular dysfunction
Cardiol. 2003 ; 100 : 149-155.
JONDEAU G., KOREWICKI J., VASILIAUSKAS D.

Effect of ivabradine in patients with left ventricular systolic dysfunction and coronary artery
disease.
Eur. Heart J. 2004 ; 25 (suppl.) –2637- : 451.
MULDER P., BARBIER S., CHAGRAOUI A., et al.

Long-term heart rate reduction induced by the selective if current inhibitor ivabradine improves
left ventricular function and intrinsic myocardial structure in congestive heart failure.
Circulation 2004 ; 109 : 1674-1679.
JONDEAU G., BOHM M., TAVAZZI L. et al.

Hemodynamic effects of ivabradine, a pure heart rate lowering agent, in patients with severe
systolic chronic heart failure receiving beta-blockers.
Abstract
DE FERRARI G.M., MAZZUERO A., AGNESINA L. et al

Favourable effects of heart rate reduction with intravenous administration of ivabradine in
patients with advanced heart failure.
European Journal of heart failure 2008; 10 : 550 – 555
SWEDBERG K., KOMAJDA M., BOHM M., et al.

Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of
ivabradine in chronic heart failure : the Systolic Heart Failure Treatment with the If inhibitor
Ivabradine Trial (SHIFT).
European Journal of Heart Failure Advance Access published November 5, 2009.
DIS-2010 23
-11-
PROCORALAN AND SUPRAVENTRICULAR ARRHYTHMIAS
PROCORALAN is the first selective and specific inhibitor of the sinus node If current that exerts
an anti-ischaemic and antianginal action by pure heart rate reduction, without altering other
parameters of cardiac function, and in particular without having a negative inotropic effect.
PROCORALAN exclusively slows the sinus node automaticity, by decreasing the slope of slow
depolarisation that precedes the action potential of the sinus node cells. It does not alter other
electrophysiological parameters and no anti-arrhythmic properties have been demonstrated to
date.
1) Atrial fibrillation
In principle, since atrial fibrillation (AF) does not originate in the sinus node, PROCORALAN
should have no direct effect on this type of arrhythmia.
In fact, pilot studies have shown firstly that PROCORALAN did not reduce acute AF episodes
by restoring normal sinus rhythm, and secondly that it did not slow down the ventricular rate in
patients in atrial fibrillation. PROCORALAN did not prevent the onset of episodes of
paroxysmal AF either (phase II studies).
Indeed, the action of PROCORALAN is specific for the sinus node and does not affect other
regions of the atrium. In addition, the If current is probably not involved in the genesis of atrial
fibrillations.
Furthermore, PROCORALAN has no effect on atrioventricular conduction and does not slow
down the rate of ventricular contraction.
Consequently, it is not recommended to prescribe PROCORALAN for patients with atrial

fibrillation or other supraventricular arrhythmias that interfere with sinus node function, as
stipulated in the authorised product information (§4.4 of the SPC).
2) Inappropriate sinus tachycardia
PROCORALAN’s mode of action affords a theoretical advantage in inappropriate sinus

tachycardia, because it enables the heart rate to be lowered while preserving all other cardiac
parameters.
However, no specific studies have been conducted to date into the usefulness of PROCORALAN
in this indication.
In the absence of available data, prescribing PROCORALAN in inappropriate sinus tachycardia
is not justified.
Furthermore, this disease often affects young women of childbearing potential. Prescribing
PROCORALAN for these female patients would require effective contraception, on account of
the embryotoxic and teratogenic effects of ivabradine observed in some animal species.
DIS-2010 24
-12-
THE VALUE OF PROCORALAN IN HEART TRANSPLANT RECIPIENTS

(CO-ADMINISTRATION OF IMMUNOSUPPRESSANTS)
PROCORALAN is the first selective and specific inhibitor of the sinus node If current, which
produces an anti-ischemic and anti-angina action by reducing only the heart rate, without
modifying the other cardiac physiological parameters, and in particular without any negative
inotropic effect.
The mode of action of PROCORALAN suggests it may be of value in heart transplant recipients
with sinus tachycardia (DOESCH, ZHANG).
The effects de PROCORALAN on heart rate reduction, exercise capacity and its safety were
observed in a prospective open-label study conducted in comparison with metoprolol in
25 heart transplant recipients (DOESCH 2007).
The patients received metoprolol (target dose = 190 mg/day) and ivabradine (target dose = 2 x
7.5 mg/day) for two 8-week periods.
Due to the heart rate reduction obtained, PROCORALAN improved the patients’ physical
ability in their daily activities and was well tolerated. In fact, more patients chose to continue
their treatment with PROCORALAN than with metoprolol.
A retrospective analysis in 26 patients with sinus tachycardia after a heart transplant showed
that PROCORALAN had reduced the heart rate by 24 bpm after 3 weeks of treatment. After
12 weeks, the left ventricular mass and the thickness of the posterior wall had decreased to a
statistically significant extent, with a tendency towards an improvement of the ejection fraction
(ZHANG).
These beneficial effects on the regression of the left ventricular mass were confirmed after 1 year
(DOESCH 2009).
The treatment for heart transplantation includes an immunosuppressant, and such agents could
give rise to drug interactions.
Ivabradine metabolism uses the CYP3A4 pathway. However, ivabradine is a very weak
inhibitor of CYP3A4 and therefore does not affect the metabolism and plasma concentrations of
other CYP3A4 substrates.
On the other hand, interaction studies have shown that plasma concentrations of ivabradine are
increased by CYP3A4 inhibitors and reduced by CYP3A4 inducers.
Amongst the immunosuppressants, cyclosporin is classified as a moderate inhibitor of CYP3A4.

In the literature, 2 to 20-fold increases have been reported in the plasma concentrations of
substrates of CYP3A4 during concomitant treatments involving cyclosporin.
Interaction tests have revealed an in vitro increase in the plasma concentrations of ivabradine by
a factor of 2.9 in the area under the curve after treatment with cyclosporin, which suggests that
there is a moderate interaction between the two molecules.
Consequently, in accordance with the PROCORALAN monograph, the concomitant use of
ivabradine with cyclosporin can be envisaged at an initial dosage of 2.5 mg twice daily, if the
resting heart rate is over 60 bpm, with monitoring of the heart rate.
As for the immunosuppressants tacrolimus, sirolimus and everolimus, their respective effects on
ivabradine metabolism by CYP3A4 have not been studied in vitro.
Nevertheless, the data in the literature describe tacrolimus as a weak inhibitor of CYP3A4 and
sirolimus as having no inhibition potential. The co-administration of these agents with
ivabradine therefore appears possible without dose adjustment.
DIS-2010 25
Finally, little data is available on everolimus. However, everolimus has already been used in
renal transplant recipients in combination with ciclosporin without any major modification of
the plasma concentrations of either agent.
In the studies conducted with PROCORALAN in heart transplant patients (DOESCH), no

pharmacokinetic interaction was reported between the immunosuppressants used (including
ciclosporin) and ivabradine.
Encl.
DOESCH A.E., CELIK S., EHLERMANN P., et al.

Heart rate reduction after heart transplantation with beta-blocker versus the selective If channel
antagonist ivabradine.
Transplantation 2007 ; 84 : 988-996
ZHANG R., HAVERICH A., STRUBER M., et al.

Effects of ivabradine on allograft function and exercise performance in heart transplant
recipients with permanent sinus tachycardia.
Clin. Res. Cardiol. 2008
DOESCH A.O., AMMON K., KONSTANDIN M., et al.

Heart rate reduction for 12 months with ivabradine reduces left ventricular mass in cardiac
allograft recipients.
Transplantation 2009; 88: 835-841
DIS-2010 26
-13-
CONTRAINDICATION IN PACEMAKER PATIENTS
PROCORALAN exerts its anti-ischaemic and antianginal effect through pure heart rate
reduction by selective and specific inhibition of the sinus node If current, the heart’s main
pacemaker current, which is responsible for the slope of the slow diastolic depolarisation of the
action potential.
PROCORALAN therefore exclusively reduces the heart rate, both at rest and during exercise,
while also preserving contractility, atrioventricular conduction and ventricular repolarisation.
Various clinical situations may be present in coronary heart disease patients with a pacemaker.
1) Pacemaker-dependent patients
Patients whose spontaneous heart rate is lower than the threshold rate of the pacemaker, due to
sinus bradycardia, bradyarrhythmia or underlying complete (third-degree) atrioventricular
block, are completely dependent on their pacemaker. Their heart rate is therefore imposed
exclusively by the pacemaker.
Since PROCORALAN acts on the sinus node, the activity of which is masked by the intracardiac
pacing of the artificial pacemaker, the drug will have no effect on pacemaker frequency and is
therefore not indicated in these patients.
2) Patients with sinus rhythm and a heart rate higher than the threshold rate of the pacemaker
When the patient’s spontaneous heart rate is higher than the threshold rate of the pacemaker,
the patient is in sinus rhythm and is therefore not pacemaker-dependent.
In patients with coronary heart disease and angina attacks, it may prove necessary to slow down
their heart rate and PROCORALAN’s usual therapeutic effect on the sinus node would be
valuable here.
Moreover, there is no reason to suspect that PROCORALAN would have any effect on the
functioning of the pacemaker itself.
Indeed, PROCORALAN acts specifically on the sinus node and there is no pacemaker atrial lead
in the sinus node. Therefore PROCORALAN cannot interfere with the functioning of this atrial
lead.
Similarly, since PROCORALAN has no ventricular effects, it cannot alter the functioning of a
pacemaker ventricular lead.
In conclusion
Although PROCORALAN has not been studied specifically in angina patients with an artificial
pacemaker, some pacemaker patients were enrolled in the phase III clinical studies.
No particular problems were observed.
Thus, it would be more correct to consider the contraindication for PROCORALAN in the
authorised product information in patients with and dependent on an artificial pacemaker as a
"non-indication".
DIS-2010 27
-14-
THE ABSENCE OF REBOUND EFFECT ON WITHDRAWAL OF TREATMENT
PROCORALAN is the first selective and specific inhibitor of the sinus node If current to produce
an anti-ischemic and anti-angina effect by reducing the heart rate alone, without altering the
other cardiac function parameters, and in particular without any negative inotropic effect.
As a result of this specific and selective mechanism of action on the If, current, PROCORALAN
has no effect on the beta-adrenergic receptors.
No rebound effect has been observed on sudden withdrawal of PROCORALAN treatment:

gradual down-titration is therefore not necessary.
The absence of rebound tachycardia with PROCORALAN not only simplifies the management
of treatment relative to beta-blocker therapy, but also reduces the risk of adverse effects
following missed doses or unscheduled gaps in medication administration.
The main plasma elimination half-life of PROCORALAN is 2 hours, and its effective half-life is
11 hours. Complete elimination of the drug is usually obtained after 5 times the plasma
elimination half-life, and so the time required for PROCORALAN to be eliminated is between
24 and 48 hours.
Encl.

Circulation 2003 ; 107 : 817-823.

DIS-2010 28
-15-
ASSOCIATION WITH BETA-BLOCKERS
PROCORALAN can be combined with beta-blockers.
PROCORALAN is indicated in symptomatic treatment of chronic stable angina pectoris in

coronary artery disease patients with normal sinus rhythm:
- in patients unable to tolerate or with a contra-indication to the use of beta-blockers
- or in combination with beta-blockers in patients inadequately controlled with an optimal
beta-blocker dose and whose heart rate is > 60 bpm.
The beneficial effects of combining PROCORALAN with betablockers in terms of anti-ischemic

efficacy, of the prevention of the cardiovascular events and of safety of use, have been
demonstrated by the ASSOCIATE and BEAUTIFUL studies, regardless of the betablocker
administered or of the dose of betablocker, as long as the resting heart rate was greater than
60 bpm.
Sotalol is the only betablocker with which it is inadvisable to associate PROCORALAN.
A recent pilot study carried out in 29 patients with stable angina (CCS I-II) with moderate left
ventricular dysfunction (LVEF 39%) and who were already receiving treatment with bisoprolol 5
mg demonstrated, after 2 months of follow-up, that adding PROCORALAN to the bisoprolol
produced a greater improvement in the exercise capacities of the patients (6-minute walking
test, exercise test) than doubling the dose of bisoprolol (AMOSOVA).
Encl.
REIL J-Ch., BOHM M.

Lancet 2008 ; 372 : 779-780.

Lancet 2008 ; 372 : 807-816.

Lancet 2008 ; 372 : 817-821.

DIS-2010 29
AMOSOVA E.N., ANDREJEV E., ZADEREIJ I.
Anti-ischemic efficacy of ivabradine in combination with bisoprolol versus uptitration of
bisoprolol.
JACC 2010 (55) - Abstract
DIS-2010 30
-16-
PREGNANCY AND BREAST-FEEDING
No data are available about the use of PROCORALAN by pregnant or breast-feeding women.
However, reproductive toxicity studies in animals have shown embryotoxic and teratogenic
effects.
PROCORALAN is therefore contraindicated in pregnancy and in young women who wish to
become pregnant.
The animal studies also show that ivabradine is secreted in breast milk.
PROCORALAN is therefore also contraindicated in breast-feeding women.
DIS-2010 31
-17-
CHILDREN
No data are available about the kinetics, efficacy and safety of PROCORALAN in children and
adolescents.
PROCORALAN must not therefore be prescribed before physiological maturity corresponding

to 15 years of age.
DIS-2010 32
-18-
THE ELDERLY
The pooled results reported from patients with coronary heart disease over 65 years of age
recruited into the phase III studies show that the efficacy of PROCORALAN in elderly subjects
is identical to that reported in the general population, in terms of heart rate reduction,
improvement of ergometric parameters, the decrease in the number of angina attacks and
nitroglycerin consumption.
A preliminary analysis was conducted on a subgroup of 232 patients over 65 years of age from
the INITIATIVE study, which compared ivabradine to atenolol over a 4-month period.
The results confirm that in this elderly population the benefits obtained with PROCORALAN on
exercise duration and the time to ST segment depression were also observed in the elderly
patients, and the drug was well tolerated.
A second analysis reported the results obtained in 838 patients over 65 years of age and
91 patients over 75 years of age from an overall population of 2,425 patients with coronary heart
disease enrolled in various phase III studies and treated with PROCORALAN at variable doses
(5 mg, 7.5 mg or 10 mg twice daily) for 3 – 4 months.
The mean reduction in heart rate was 11.6 bpm in the patients who were over 65 years of age, 12
bpm (15%) in the patients over 75 years of age, and 11.3 bpm (14.5%) in the total population.
The reduction in the number of angina attacks (56.2% and 53.2%) and in nitroglycerin
consumption (51.5% and 57.3%) in patients over 65 years of age and over 75 years of age,
respectively, were equivalent to those observed in the overall population (-59.4% angina attacks
and -53.7% nitroglycerin tablets).
Furthermore, the antianginal efficacy of PROCORALAN in elderly subjects was accompanied by
the same safety profile as in the general population.
Finally, these results were confirmed in a third analysis carried out in 382 coronary patients over
80 years of age. After 4 months of treatment, PROCORALAN, at a dose of 2.5 mg, 5 mg or
7.5 mg twice daily, produced a mean significant reduction in the heart rate of 11.9 bpm, in the
number of angina attacks by 73% and in the consumption of trinitrine by 74%, combined with
very good safety.
However, as the patient cohort containing the oldest subpopulation is limited, as a

precautionary measure the minimum dose of PROCORALAN (2.5 mg twice daily, i.e. one half-
tablet of the 5-mg strength twice daily) is recommended when starting treatment in subjects over
75 years of age; the dose may be increased later if necessary.
Encl.
TENDERA M., FOX K., TARDIF J., FORD I.

Anti-ischemic and antianginal efficacy of ivabradine, a selective and specific If current inhibitor,
in elderly patients with stable angina.
American Heart Association Congress 2006; Abstract 3363.

Cardiology 2009; 114: 116-125
KOESTER R., KAEHLER J., MEINERTZ T.

Ivabradine in octogenarians: a subgroup analysis of the REDUCTION-Study (Reduction of
Ischemic Events by Reduction of Heart Rate in the Treatment of Stable Angina with Ivabradine).
European Heart Journal 2009; 30 (supplement); P4510
DIS-2010 33
-19-
RENAL IMPAIRMENT
The pharmacokinetics of ivabradine are relatively unaltered by mild to moderate renal

impairment (creatinine clearance between 15 and 60 ml/min), given the small contribution of
renal clearance (approximately 20%) to the total elimination of ivabradine and its major
metabolite.
The total clearance is approximately 400 ml/min and renal clearance approximately 70 ml/min.
The metabolites are excreted in equal quantities in the faeces and urine.
The ivabradine molecule is not removed by dialysis.
The efficacy and safety data collected from patients with moderate renal impairment enrolled in
the phase III studies, treated with PROCORALAN at a dose of 2.5 mg, 5 mg or 7.5 mg twice
daily, was specifically analysed.
This population contained 371 patients with a creatinine clearance of less than 60 ml/min. Of
these, 61 patients had a creatinine clearance between 30 and 45 ml/min (mean treatment
duration: 178 days ± 135) and 8 patients had a creatinine clearance between 15 and 30 ml/min
(mean treatment duration: 227 days ± 143) (unpublished data).
In these renally impaired patients, PROCORALAN lowered the heart rate and the weekly
number of angina attacks to a similar extent as in the general population. PROCORALAN also
improved all the exercise test parameters.
Similarly, PROCORALAN did not cause any particular adverse events, aside from its expected
effects (bradycardia and phosphene-like luminous phenomena). These effects occurred with a
similar frequency to that observed in the general population. No variation in blood pressure or
QTc interval was observed.
In the subgroup of patients with severe renal impairment, no cases of bradycardia were
reported. Mild visual effects were noted in 3 patients. No events requiring cessation of treatment
occurred.
In conclusion, PROCORALAN is as effective in patients with renal impairment as in the general

population and remains well tolerated by these patients. Therefore, mild to moderate renal
impairment (creatinine clearance greater than 15 ml/min) does not require dose adjustment.
However, in the absence of data, the prescription of PROCORALAN is not recommended in

patients whose creatinine clearance is less than 15 ml/min and in patients on haemodialysis
(ivabradine and its metabolite are not dialyzable).
Similarly, no studies have been conducted in renal transplant recipients.
DIS-2010 34
-20-
HEPATIC IMPAIRMENT
When transaminase elevation (ALT or AST more than 1.5-fold normal levels) was used to select
patients with hepatic impairment (n = 129), no relevant differences in plasma exposure were
observed between patients with elevated transaminases and the general population.
In patients with mild hepatic impairment (defined as a Child Pugh score of up to 7), the levels of
free ivabradine and its major active metabolite are approximately 20% higher than those in
subjects with normal hepatic function.
The data are insufficient in order to be able to draw conclusions in patients with moderate
hepatic impairment.
No data are available on patients with severe hepatic impairment.
PROCORALAN dose adjustment is therefore not required in patients with mild hepatic
impairment.
In patients with moderate hepatic impairment, the minimum dose of PROCORALAN (2.5 mg
twice daily) is recommended at the start of treatment.
However, in the absence of data, PROCORALAN is contraindicated in patients with severe
hepatic impairment, due to the large foreseeable increase in ivabradine plasma levels.
DIS-2010 35
-21-
RESPIRATORY FAILURE (ABSENCE OF BRONCHOSPASM)
The efficacy and safety profile of PROCORALAN in asthmatic patients is similar to that in the
general population.
By virtue of its specific and selective mode of action on the If, current, PROCORALAN has no
effect on beta-adrenergic receptors.
Thus, PROCORALAN has no effect on the smooth muscle cells of the bronchial wall. It does not
cause bronchoconstriction and may be prescribed in angina patients with asthma or chronic
obstructive pulmonary disease.
A specific study of the effects of PROCORALAN in asthmatic patients was conducted (BABU).
No change was observed in ivabradine pharmacokinetics in this population.
Furthermore, PROCORALAN did not change the parameters measured in the pulmonary
function tests (peak expiratory flow rate and forced expiratory volume in 1 second).
The analysis of an asthmatic subpopulation of 137 patients from the phase III clinical trials
showed that PROCORALAN, at a dose of 5 mg, 7.5 mg or 10 mg twice daily, is as effective and
well tolerated as in the overall population.
The mean reduction in the heart rate was 11.9 bpm (14.9%) in asthmatic coronary patients, and
11.3 bpm (14.5%) in the total population. The reduction in the number of angina attacks (54%)
and nitroglycerin consumption (58.3%) was equivalent to that obtained in the general
population (59.4% and 53.7%, respectively).
The acceptability of the treatment in asthmatic patients was the same as in the general
population.
Encl.
BABU K.S., GADZIK F., HOLGATE S.T.

Absence of respiratory effects with ivabradine in patients with asthma
Br J Clin Pharmacol. 2008; 66 (1) : 96-101

Cardiology 2009; 114: 116-125
DIS-2010 36
-22-
DIABETIC SUBJECTS
PROCORALAN maintains its antianginal and anti-ischaemic efficacy and its safety profile in
diabetic patients with coronary heart disease.
The effects of PROCORALAN were studied in 535 diabetic patients with coronary heart disease
from the phase III clinical studies, treated with PROCORALAN over periods ranging from 3 to
12 months (BORER).
The heart rate reduction obtained in diabetic patients was equivalent to that obtained in the
total population: -11.6 bpm versus -11.3 bpm, i.e. approximately -15%. The exercise test results
(total exercise duration, time to angina onset, and time to 1 mm ST segment depression) were
equivalent in the two groups. The number of angina attacks was also reduced to a similar extent
in both groups (-60% in the total population and -61% in the diabetic patients with coronary
heart disease).
No specific clinical or biological intolerance was observed in the diabetic patients.

PROCORALAN preserves the carbohydrate metabolism, and actually reduces the level of
HbA1C, in contrast to atenolol and amlodipine, which increase it (significant inter-group
difference, p=0.049 ivabradine vs. atenolol, and p<0.001 ivabradine vs. amlodipine).
PROCORALAN had no effect on the warning signs of hypoglycemia.
No risk of exacerbation of diabetic retinopathy is expected.
Encl.
BORER J.S., TARDIF J.C.

Efficacy of ivabradine, a selective If inhibitor, in patients with chronic stable angina pectoris and
diabetes mellitus
Am. J. Cardiol. 2010; 105: 29-35
DIS-2010 37
-23-
SPORTSMEN AND SPORTSWOMEN
The therapeutic indication for PROCORALAN does not really lend itself to use in people
engaged in competitive sports.
No data is currently available from sportsmen or sportswomen without coronary heart disease.
However, ivabradine, the active pharmaceutical ingredient in PROCORALAN, is not currently

identified on the prohibited list of the International Olympic Committee for anti-doping testing.
The main plasma elimination half-life of PROCORALAN is 2 hours, and it has an effective half-
life of 11 hours. As complete elimination of a drug is usually obtained after 5 times the plasma
elimination half-life, PROCORALAN treatment should be stopped at least 48 hours before the
race.
No rebound effect has been observed on sudden withdrawal of PROCORALAN treatment:

gradual down-titration is therefore not necessary.
DIS-2010 38
-24-
CLINICAL AND BIOLOGICAL ACCEPTABILITY
In clinical trials, PROCORALAN has been shown to have an excellent clinical and biochemical
tolerability profile.
1) Clinical tolerability
The most common adverse effects observed are dose-dependent and related to the
pharmacological effect of PROCORALAN: bradycardia and phosphenes.
Bradycardia occurs rarely. It is estimated to occur in 3.3% of patients and is observed

particularly during the first 2 or 3 months of treatment. It only leads to treatment cessation in
less than 1% of cases, at doses of 5 mg twice daily and 7.5 mg twice daily.
No severe bradycardia (HR ≤ 40 bpm) has been observed at a dose of 5 mg twice daily. Only
0.5% of patients have developed severe bradycardia at a dose of 7.5 mg twice daily (compared to
1.7% with atenolol).
In the study of the association of PROCORALAN with 50 mg of atenolol, only 1.1% of the
withdrawals from the study due to bradycardia in the ivabradine group were reported.
In the BEAUTIFUL study, which assessed the effects of PROCORALAN in reducing the
cardiovascular morbidity-mortality in 10,917 coronary artery disease patients with systolic left
ventricular dysfunction, in the ivabradine group, the onset of symptomatic bradycardia led to
withdrawals from the trial in only 2.7% of cases. Furthermore, the number of serious adverse
events was the same in both groups. This study confirmed the good safety profile of
PROCORALAN associated with betablockers.
The low incidence of severe bradycardia is due to the fact that the action of PROCORALAN on
the heart rate is dose-dependent, but limited by a plateau effect. Furthermore, the higher the
initial resting heart rate, the greater the heart rate reduction produced by PROCORALAN,
which limits the risk of bradycardia even further.
In practice, if the heart rate decreases persistently below 50 beats per minute (bpm) at rest or if
the patient exhibits bradycardia-related symptoms (dizziness, fatigue or hypotension, etc.), the
dose must be reduced to 2.5 mg twice daily (i.e. one half-tablet of the 5-mg strength twice daily).
Treatment must be discontinued if the heart rate remains below 50 bpm or if the bradycardia-
related symptoms persist.
The other adverse effects reported are essentially cardiac:

- as with any bradycardic treatment, heart rate reduction may also reveal ventricular
premature beats (3%),
- first-degree atrioventricular block (1.4%). A decrease in heart rate can reveal an underlying
first-degree AV block.
The occurrence of phosphenes, meanly in 14.5% of cases, does not affect normal activity or the
patient’s quality of life: fewer than 1% of patients discontinued the treatment due to
phosphenes.
Phosphenes are described as transient enhanced luminosity in a limited area of the visual field.
Phosphenes are purely functional, and do not correspond to any organic damage to the retina.
Inhibition of the retinal Ih current enhances the retinal response to sudden changes in light
intensity, with the appearance of phosphenes.
DIS-2010 39
In general, the phosphenes caused by PROCORALAN are mild to moderate in intensity, and
occur during the first two months of treatment, mainly in the evening and at night, during
changes in light intensity. They are transient, i.e. they are not continuous over the course of the
day and furthermore they do not continue for long, generally not exceeding one week. They are
usually observed with the highest doses of ivabradine and resolve during treatment in most
cases (77.5%). Subsequent recurrence of this effect has been observed in rare cases. They always
resolve within 48 hours of stopping the treatment.
2) Biological tolerability
Renal function is preserved with PROCORALAN.
PROCORALAN does not alter carbohydrate or lipid metabolism.
The changes in the biochemical and hematological parameters analyzed during the clinical trials
were generally minor, of no clinical pertinence, and comparable to those reported in the control,
placebo or comparator treatment groups.
These safety data have been confirmed in the long term (1 year) in a study conducted in
386 patients with stable angina pectoris: no clinically significant variation was reported for blood
pressure, body weight, blood biochemistry or haematological parameters (LOPEZ-BESCOS).
Encl.

Circulation 2003 ; 107 : 817-823
Investigators.
Eur. Heart J. 2005 ; 26 : 2529-2536

Long-term safety and efficacy of ivabradine in patients with chronic stable angina.
Cardiology 2007 ; 108 : 387-396.

Lancet 2008 ; 372 : 807-816.
DIS-2010 40
-25-
VISUAL TOLERANCE
The main adverse effects reported with PROCORALAN are phosphene-like visual effects; rare
cases of blurred vision have also been reported.
Phosphenes are described as transient enhanced luminosity in a limited area of the visual field.
Phosphenes are purely functional, and do not correspond to any organic damage to the retina.
This effect is due to the presence of Ih channels in the retina, which are closely related to the If
channels of the sinus node, and which are involved in the retinal response to light stimuli.
Inhibition of the retinal Ih current enhances the retinal response to sudden changes in light
intensity, with the appearance of phosphenes.
PROCORALAN binds to HCN4 and HCN1 channels, which are responsible for the sinus node If
and retinal Ih ionic currents, respectively.
In general, the phosphenes induced by PROCORALAN are mild to moderate in intensity, and
occur during the first two months of treatment, mainly in the evening and at night, during
changes in light intensity. They are transient, i.e. they are not continuous over the course of the
day and furthermore they do not continue for long, generally not exceeding one week. They are
usually observed with the highest doses of ivabradine and resolve during treatment in most
cases (77.5%). Subsequent recurrence of this effect has been observed in rare cases. They always
resolve of stopping the treatment.
In the study of the association of PROCORALAN with 50 mg of atenolol, the occurrence of

visual symptoms (phosphenes and blurred vision) was spontaneously reported by 2% of
patients in the ivabradine group versus 0.9% in the placebo group.
In the BEAUTIFUL study, visual symptoms requiring discontinuation of the treatment occurred
in 0.5% of the patients treated with PROCORALAN versus 0.2% in the placebo group. These
symptoms all disappeared when the treatment was stopped.
The occurrence of phosphenes, meanly in 14.5% of cases, does not affect normal activity or the
patient’s quality of life and only result in discontinuation of the treatment in fewer than 1% of
cases.
Encl.

Circulation 2003 ; 107 : 817-823
Investigators.
Eur. Heart J. 2005 ; 26 : 2529-2536

DIS-2010 41
Lancet 2008 ; 372 : 807-816.
DIS-2010 42
-26-
WHAT TO DO IN THE EVENT OF AN OVERDOSE
PROCORALAN is the first selective and specific inhibitor of the sinus node If current which acts
purely through heart rate reduction (both at rest and during exercise) without altering other
parameters of cardiac function, and in particular has no negative inotropic effect. Contractility,
atrioventricular conduction and ventricular repolarisation are preserved.
The heart rate reduction induced by PROCORALAN is dose-dependent, and the higher the
baseline heart rate, the greater its effect.
PROCORALAN overdose carries a risk of severe and prolonged bradycardia, which requires
symptomatic treatment in a specialised environment.
If the patient’s heart rate is excessively low, intravenous sympathomimetic drugs such as
isoprenaline or dobutamine can be used for the symptomatic treatment of severe bradycardia
(< 40 bpm).
Temporary cardiac electrical pacing may be necessary.
DIS-2010 43
-27-
DISEASE WHAT TO DO IF CARDIAC OCCURS
1) Myocardial infarction and unstable angina
PROCORALAN is the first selective and specific inhibitor of the sinus node If current which acts
by reducing the heart rate alone, without affecting the other parameters of cardiac function and,
in particular, which has no negative inotropic effect.
During its acute phase, myocardial infarction is a contraindication for PROCORALAN.

Indeed, because the acute phase of myocardial infarction was an exclusion criterion in the
clinical studies, no data are currently available about the efficacy and tolerability of
PROCORALAN in such circumstances.
Therefore if myocardial infarction occurs during PROCORALAN treatment, the treatment must
be suspended temporarily for the time required for the patient’s haemodynamic condition to
stabilise. Reintroduction or introduction of the treatment may be considered once the acute
episode is over, when the patient’s clinical and haemodynamic condition has stabilised, taking
into account the patient’s clinical condition and complying with the contraindications that apply
to the medicinal product.
PROCORALAN was developed as an antianginal and anti-ischaemic treatment in patients with

chronic stable angina pectoris with sinus rhythm.
No studies have yet been conducted in unstable angina.
Therefore, in the absence of available data, if unstable angina develops in a patient treated with
PROCORALAN, discontinuation of the treatment is recommended.
2) Heart failure
- Chronic heart failure
Various experimental studies have shown that cardiac output is maintained during
PROCORALAN treatment, in spite of the reduced heart rate (MANZ, JONDEAU, MULDER,
SIMON). Indeed, since PROCORALAN has no negative inotropic or lusitropic effect, it increases
the stroke volume. In addition, PROCORALAN does not affect blood pressure or peripheral
vascular resistance.
The results of a study carried out in patients with severe heart failure (NYHA stages III and IV–
EF<35%) demonstrate that PROCORALAN, combined with conventional treatment,
significantly reduces the heart rate, that it is well tolerated and improves the patients' left
ventricular function (JONDEAU).
In a second study carried out in 10 patients with severe heart failure (NYHA stage III– mean EF
=21%) who were already receiving the optimum treatment, the intravenous administration of
PROCORALAN led to a reduction in the heart rate, and an increase in the stroke volume, thus
making it possible to maintain the cardiac output (DE FERRARI).
These encouraging preliminary results led to the continuation of the development of

PROCORALAN in heart failure. The aim of the SHIFT study is to evaluate the effects of
PROCORALAN on cardiovascular events in patients presenting with moderate to severe
chronic heart failure (NYHA stages II to IV), whether of ischemic or non-ischemic origin.
DIS-2010 44
- Cardiac decompensation
If pulmonary edema occurs in a patient treated with PROCORALAN this calls for
discontinuation of the treatment.
The heart failure must be stabilized with an appropriate treatment before envisaging treatment
with PROCORALAN.
The administration of PROCORALAN is contraindicated in NYHA class III-IV heart failure.
3) Non-sinus arrhythmias
PROCORALAN exclusively slows the sinus node automaticity, by decreasing the slope of slow
depolarisation that precedes the action potential of the sinus node cells.
PROCORALAN does not alter other electrophysiological parameters and no anti-arrhythmic
properties have been demonstrated to date.
Given our current state of knowledge, it is therefore not recommended to prescribe

PROCORALAN for patients with supraventricular arrhythmias that interfere with sinus node
function (§ 4.4 SPC).
Therefore, if supraventricular premature beats, chronic atrial fibrillation or atrial flutter occur
during PROCORALAN treatment, the treatment will no longer be of value and should be
discontinued.
As with any bradycardic treatment, the heart rate reduction obtained with PROCORALAN may
reveal ventricular premature beats (VPB), but PROCORALAN should not have a harmful effect.
If VPBs occur, it is therefore not necessary to discontinue the treatment.
4) Conduction disturbances
PROCORALAN acts specifically on the sinus node, and does not affect atrioventricular or
intraventricular conduction, myocardial contractility or ventricular repolarisation.
Consequently, sinoatrial block and sick sinus syndrome are contraindications for the
prescription of PROCORALAN.
Ivabradine administration does not affect the PR and QRS intervals, atrial conduction or
refractory periods, the atrioventricular node, the His-Purkinje system or the ventricles (CAMM).
Therefore, PROCORALAN can be prescribed for patients with first-degree atrioventricular block
or an intraventricular conduction disturbance (bundle branch block).
However, the presence of these abnormalities may indicate underlying cardiac disease and any
precautions will then be related to the disease in question.
However, the prescription of PROCORALAN is inadvisable for patients with second-degree

atrioventricular block and contraindicated in third-degree atrioventricular block, which requires
an artificial pacemaker.
Encl.
SIMON L., GHALEH B., PUYBASSET L., GIUDICELLI J.F., BERDEAUX A.

J. Pharmacol. Exper. Therap. 1995 ; 275 (2) : 659-666.
DIS-2010 45
MANZ M., REUTER M., LAUCK G., OMRAN H., JUNG W.
A single intravenous dose of ivabradine, a novel if inhibitor, lowers heart rate but does not
depress left ventricular function in patients with left ventricular dysfunction
Cardiol. 2003 ; 100 : 149-155.
JONDEAU G., KOREWICKI J., VASILIAUSKAS D.

Effect of ivabradine in patients with left ventricular systolic dysfunction and coronary artery
disease.
Eur. Heart J. 2004 ; 25 (suppl.) –2637- : 451.
MULDER P., BARBIER S., CHAGRAOUI A., et al.

Long-term heart rate reduction induced by the selective if current inhibitor ivabradine improves
left ventricular function and intrinsic myocardial structure in congestive heart failure.
Circulation 2004 ; 109 : 1674-1679.
JONDEAU G., BOHM M., TAVAZZI L. et al.

Hemodynamic effects of ivabradine, a pure heart rate lowering agent, in patients with severe
systolic chronic heart failure receiving beta-blockers.
Abstract
DE FERRARI G.M., MAZZUERO A., AGNESINA L. et al

Favourable effects of heart rate reduction with intravenous administration of ivabradine in
patients with advanced heart failure.
European Journal of heart failure 2008; 10 : 550 - 555
CAMM A.J., LAU C.P.

Electrophysiological effects of a single intravenous administration of ivabradine (S16257) in
adult patients with normal baseline electrophysiology.
Drugs R&D 2003 ; 4 (2) : 83-89.
SAVELIEVA I., JONES S., DOUGAL K., et al.

Noninvasive electrophysiological study of ivabradine (NESI) in patients with dual chamber
pacemakers : effects on ventricular repolarization.
J. Am. Coll. Cardiol., 2006 ; 47 : 27A (abstract).
SWEDBERG K., KOMAJDA M., BOHM M., et al.

Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of
ivabradine in chronic heart failure : the Systolic Heart Failure Treatment with the If inhibitor
Ivabradine Trial (SHIFT).
European Journal of Heart Failure Advance Access published November 5, 2009.
DIS-2010 46
-28-
ASSOCIATION / INTERACTIONS WITH

COMMON CARDIOLOGY DRUGS
1) Drug treatments that improve the prognosis in coronary artery disease
The benefits of combining PROCORALAN with betablockers, in terms of the improvement in

the exercise test parameters and the prevention of cardiovascular events, have been
demonstrated by the ASSOCIATE and BEAUTIFUL studies, together with good safety of use.
PROCORALAN is indicated in symptomatic treatment of chronic stable angina pectoris in

coronary artery disease patients with normal sinus rhythm:
- in patients unable to tolerate or with a contra-indication to the use of beta-blockers
- or in combination with beta-blockers in patients inadequately controlled with an optimal
beta-blocker dose and whose heart rate is > 60 bpm.
Sotalol is the only betablocker that it is inadvisable to combine with PROCORALAN.
PROCORALAN can be combined with aspirin and with platelet antiaggregants.

In a specific study, PROCORALAN did not alter the platelet anti-aggregant properties of
aspirin.
Specific studies of interactions did not reveal any drug interaction between PROCORALAN and
various statins, in particular atorvastin, cerivastatin, lovastatin and simvastatin.
PROCORALAN is metabolized solely by CYP3A4, and is a very weak inhibitor of this
cytochrome. Ivabradine had no influence on the metabolism and plasma concentrations of other
substrates of CYP3A4, whether these are weak, moderate or strong inhibitors.
The mechanism of elimination of the statins varies from drug to drug. The metabolism of statins
involves CYP3A4, CYP2C9 or the hepatic transporter known as Organic Anion Transporting
Polypeptide (OATP-C).
In particular, pravastatin and rosuvastatin are not metabolized at all, and are eliminated by
biliary secretion involving the transporter OATP-C.
This means that PROCORALAN can be used concomitantly with statins.
PROCORALAN can be combined with angiotensin-converting enzyme inhibitors.

In the phase-III studies, ACE inhibitors were authorized and commonly associated with
ivabradine. No interaction was observed.
To conclude, PROCORALAN can be associated with the drugs of the BASIC protocol
(ASSOCIATE, BEAUTIFUL).
2) Amiodarone
Amiodarone is one of the medicinal products not recommended for co-administration with
PROCORALAN, due to pharmacodynamic interactions.
Indeed, amiodarone, a class III anti-arrhythmia agent, can prolong the QT interval. Prolongation
of the QT interval may by potentiated by the heart rate lowering effect of PROCORALAN,
exposing the patient to the risk of torsades de pointes.
In fact, the co-administration of amiodarone with bradycardic calcium-channel blockers and
with beta-blockers (apart from sotalol which is contraindicated) requires special precautions.
DIS-2010 47
In practice, due to accumulation of amiodarone in the tissues when administered for long
periods, the co-administration of PROCORALAN must be avoided in patients who have already
been treated for several months with amiodarone. Nevertheless, where this combination is
essential (coronary patients who would otherwise remain ischaemic and tachycardic),
PROCORALAN can be introduced at a dose of 2.5 mg morning and evening, with heart rate and
ECG monitoring.
However, the simultaneous introduction of PROCORALAN and amiodarone, or adding

amiodarone to existing PROCORALAN treatment is contraindicated.
3)Calcium channel blockers
PROCORALAN can be associated with calcium-channel inhibitors that do not reduce heart rate
(dihydropyridines).
In contrast, the association of PROCORALAN with heart rate reducing calcium channel blockers
such as diltiazem or verapamil is not recommended, due to the risk of pharmacokinetic
interactions.
Diltiazem and verapamil are moderate inhibitors of CYP3A4, and the metabolism of
PROCORALAN also involves the pathway of this cytochrome.
Specific interaction studies in healthy volunteers and in treated patients have shown that the
combination of PROCORALAN with bradycardiac calcium channel blockers leads to an increase
in the plasma concentrations of ivabradine, with the consequence of an additional 5-bpm
reduction of the heart rate.
4) Other anti-arrhythmics
The combination of PROCORALAN with anti-arrhythmics that can prolong the QT interval,
such as the class Ia and III anti-arrhythmics, is not recommended.
The prolongation of the QT interval can be reinforced by the reduction in heart rate induced by
PROCORALAN, which carries a risk of wave burst arrhythmia.
No data is available about the association of PROCORALAN with flecaine, a class-Ic anti-
arrhythmic, but a theoretical risk that the QT and/or QRS intervals will be prolonged cannot be
excluded.
The association of PROCORALAN with diltiazem and with verapamil (class-IV

antiarrhythmics) is not recommended, due to the risk of pharmacokinetic interactions.
Sotalol is the only betablocker that it is inadvisable to associate with PROCORALAN.
In the light of current knowledge, the association of PROCORALAN with some antiarrhythmics
calls for electrocardiographic monitoring.
5) Nitrates
PROCORALAN can be combined with nitrate derivatives.

In phase-III clinical trials, short-acting and long-acting nitrate derivatives, and molsidomine,
have been combined with PROCORALAN, without revealing any problems related to safety of
use (LOPEZ-BESCOS).
DIS-2010 48
6) Digoxin
PROCORALAN can be associated with digoxin.

Indeed, specific studies of the interaction with digoxin have demonstrated the absence of any
clinically significant pharmacokinetic and pharmacodynamic interaction with ivabradine.
Furthermore, no clinically significant effect of ivabradine has been observed on the
pharmacokinetics or pharmacodynamics of digoxin.
Encl.
REIL J-Ch., BOHM M.

Lancet 2008 ; 372 : 779-780.

Lancet 2008 ; 372 : 807-816.

Lancet 2008 ; 372 : 817-821.

Long-term safety and efficacy of ivabradine in patients with chronic stable angina.
Cardiology 2007 ; 108 : 387-396.
DIS-2010 49
-29-
ASSOCIATION WITH SILDENAFIL (VIAGRA)
From a pharmacokinetic point of view, the metabolism of ivabradine, the active substance of
PROCORALAN, and that of sildenafil, the active substance of VIAGRA, both use the
cytochrome P450 pathway, principally CYP3A4, and both substances have a very slight
inhibiting effect on this cytochrome.
The result is that ivabradine does not influence the metabolism or plasma concentrations of the
other substrates metabolized by CYP3A4, regardless of whether they are weak, moderate or
powerful inhibitors. Thus, the metabolism of sildenafil should not be modified in the presence of
ivabradine.
An unpublished study of the specific interaction between PROCORALAN and VIAGRA in

patients suffering from coronary heart disease has demonstrated a slight increase of the plasma
exposure of the patients to ivabradine as a result of taking sildenafil although this limited effect
does not have any impact on the lowering of the heart rate.
This results suggest that PROCORALAN and VIAGRA can be combined, if the patient’s heart
condition permits the prescription of VIAGRA, and their combination does not call for any
dosage adjustment or increased monitoring of the heart rate.
DIS-2010 50
-30-
COMPARISON WITH BETA-BLOCKERS
The properties of PROCORALAN differ from those of betablockers.
1) Pharmacological differences
Betablockers are specific competitive antagonists of beta-adrenergic catecholamine receptors.

Their cardiac effects are characterized by negative chronotropic, inotropic, dromotropic and
bathmotropic effects.
Their antiangina activity is the consequence of reducing the oxygen needs of the myocardium
by a combination of negative chronotropic and inotropic effects.
Betablockers do not increase the oxygen supply much, due to their negative lusitropic effect and
by limiting coronary artery vasodilatation during exercise.
PROCORALAN is the first selective and specific inhibitor of the sinus node If current.
PROCORALAN reduces the heart rate alone, without affecting the other parameters of cardiac
function and, in particular, which has no negative inotropic effect.
PROCORALAN has no effect on blood pressure.
PROCORALAN has no negative lusitropic effect, either at rest or during exercise, which
therefore enables better ventricular myocardial relaxation and therefore better perfusion of the
subendocardial layers of the myocardium, which are most sensitive to ischaemia. Furthermore,
PROCORALAN preserves coronary artery vasodilatation during exercise (SIMON).
Not only does PROCORALAN reduce the requirement of the myocardium for oxygen and
substrates, but it also increases myocardial oxygen supply.
Experimental findings demonstrate that solely reducing the heart rate with PROCORALAN
reduces oxidative stress, improves endothelial function and reduces the progression of
atherosclerosis (DROUIN, CUSTODIS).
2) Clinical differences
THE INITIATIVE study demonstrated that the antianginal and anti-ischaemic efficacy of
PROCORALAN is at least equal to that of atenolol (reference betablocker).
After 4 months of treatment, a 2/3 reduction in the number of angina attacks was observed with
both ivabradine and atenolol (TARDIF). The results of the treadmill exercise test performed at
baseline, after 4 weeks and at the end of the trial, showed an increase in exercise duration in
favour of ivabradine (p<0.001 non-inferiority).
This study provided evidence that for equal heart rate reduction, the anti-ischaemic efficacy of
PROCORALAN is greater than that of atenolol, even though it has no negative inotropic effect,
due to the fact that PROCORALAN considerably increases oxygen supplies to the myocardium
(LE HEUZEY).
PROCORALAN is the first antiangina drug shown to reduce the risk of myocardial infarction in
patients with stable angina, whether they are or are not receiving a betablocker (FOX). The
betablockers have not demonstrated any benefits in terms of reducing cardiovascular
morbidity/mortality in stable angina, but in post-infarction and in heart failure (ESC guidelines
2006).
Due to its specific and selective action on the If current, PROCORALAN has no effect on beta-
adrenergic receptors, which means it is better tolerated than beta-blockers. PROCORALAN can
be administered to all patients with stable coronary artery disease.
DIS-2010 51
PROCORALAN does not cause bronchoconstriction and can be prescribed for coronary patients
with asthma or chronic obstructive pulmonary disease.
PROCORALAN has no vasoconstrictive effect. There is no risk of it exacerbating occlusive
peripheral arterial disease or Raynaud’s syndrome.
Similarly, PROCORALAN does not cause erectile dysfunction.
Carbohydrate and lipid metabolism are preserved with PROCORALAN therapy, which is an
advantage for diabetic patients with coronary disease.
Finally, there is no sympathetic hyperactivity-type rebound effect associated with sudden
withdrawal of PROCORALAN treatment.
Encl.
SIMON L., GHALEH B., PUYBASSET L., et al.

COLIN P., GHALEH B., HITTINGER L., et al.

Differential effects of heart rate reduction and beta-blockade on left ventricular relaxation during
exercise.
Am. J. Physiol. Heart Circ. Physiol. 2002 : 282 : H672-679
COLIN P., GHALEH B., MONNET X.

Contributions of heart rate and contractility to myocardial oxygen balance during exercise.
Am. J. Physiol. Heart Circ. Physiol. 2003 ; 284 : H676-H682.
COLIN P., GHALEH B., MONNET X., et al.

Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and
diastolic time in exercising dogs.
BERDEAUX A., COLIN P., MONNET X., GHALEH B.

Fréquence cardiaque et ischémie myocardique expérimentale.
Thérapie 2004 ; 59 (5) : 507-510.
MONNET X., COLIN P., GHALEH B., et al.

Heart rate reduction during exercise-induced myocardial ischaemia and stunning.
Eur. Heart J. 2004 ; 25 : 579-586.
TARDIF J.C., FORD I., TENDERA M., et al. for the INITIATIVE Investigators.
Eur. Heart J. 2005 ; 26 : 2529-2536
DROUIN A., GENDRON M.E., THORIN E., et al.

Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic
mice.
Br. J. Pharmacol. 2008 ; 154 : 749-757.
CUSTODIS F., BAUMHAKEL M., SCHLIMMER N. et al.

Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and
prevents atherosclerosis in apolipoprotein E-deficient mice.
Circulation 2008 ; 117 : 2377-2387.

DIS-2010 52
Guidelines on the management of stable angina pectoris : executive summary.

The task force on the management of stable angina pectoris of the European Society of
Cardiology.
Eur. Heart J. 2006 ; 27 : 1341-1381.
DIS-2010 53

Coralan - SPC

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PROCORALAN

0. Data sheet for PROCORALAN............................................................................................... 2

DATA SHEET FOR PROCORALAN

1°) After single-dose administration

- Animal species (male animals) : mouse, rat, dog.

Species Observed max. non-lethal dose Observed min. lethal dose

- Probable cause of death (rodents, dog): neurobehavioural changes and death;

- NOAEL doses (mg/kg/day) (no observable adverse effect level)

Studies (duration) 4 weeks 13 weeks 26 weeks 52 weeks

- Toxic effects observed at doses > NOAEL doses:

- Effect on the heart:

- Effect on the visual system:

- Effect on other organs:

- In vitro and in vivo genotoxicity:

1°) Assay method for plasma and urine

- Storage conditions : plasma = at least 26 months at –18 °C

- Assay technique : solid phase extraction followed by

2°) The main pharmacokinetic parameters of ivabradine

The kinetics are linear for both time and dose.

Ivabradine is extensively metabolised, exclusively by the cytochrome CYP3A4;

4°) Dialysis and activated charcoal

- Dialysability: ivabradine is not removed by dialysis.

- Absorption by activated charcoal: ????

POSOLOGY AND METHOD OF ADMINISTRATION

Crushing the tablets

Similarly, in cases of polypharmacy it is preferable not to mix PROCORALAN powder with a

KINETIC CHARACTERISTICS (+ CYTOCHROME P450)

The volume of distribution at steady-state is close to 100 litres.

MECHANISM OF ACTION ON THE If CURRENT AND HEART RATE

1) The HCN channels

YU H., CHANG F., COHEN I.S.

YU H., CHANG F., COHEN I.S.

BOIS P., BESCOND J., RENAUDON B., LENFANT J.

SHI W., WYMORE R., YU H. et al.

MOOSMANG S., STIEBER J., ZONG X., et al.

BABUTY D., ARGIBAY J.

BIEL M., SCHNEIDER A., WAHL C.

MICHELS G., FIKRET E., KHAN I., et al.

COUETTE B., MARGER L., NARGEOT J., MANGONI M.E.

THOLLON C., BEDUT S., VILLENEUVE N. et al.

CERVETTO L., DEMONTIS G.C., GARGINI C., et al.

2) Inhibition of the I f current by ivabradine

In contrast to zatebradine, the development of which has been suspended, PROCORALAN

BOIS P., BESCOND J., RENAUDON B., LENFANT J.

BABUTY D., ARGIBAY J.

BUCCHI A., BARUSCOTTI M., DIFRANCESCO D.

DIFRANCESCO D., CAMM J.A.

COUETTE B., MARGER L., NARGEOT J., MANGONI M.E.

PRESERVATION OF CARDIAC ELECTROPHYSIOLOGY

1) Preservation of cardiac electrophysiology

In particular, ivabradine administration has no effect on the PR or QRS intervals, atrial

2) Preservation of myocardial contractility

As it has no negative inotropic effect, PROCORALAN increases the duration of effective

3) Preservation of blood pressure and peripheral resistance

SIMON L., GHALEH B., PUYBASSET L., et al.

MONNET X., GHALEH B., COLIN P., et al.

COLIN P., GHALEH B., HITTINGER L., et al.

CAMM A.J, LAU C.P.

COLIN P., GHALEH B., MONNET X.

BORER J.S., FOX K., JAILLON P.

COLIN P., GHALEH B., MONNET X., et al.

BERDEAUX A., COLIN P., MONNET X., GHALEH B.