| AMERICAN DRUGS | ANATOMY | HEALTH TOPICS | HIV/AIDS GLOSSARY | DISEASES | HEALTH ARTICLES | GENOME | OCCUPATIONS |

Procoralan

Spanish Simplified Chinese French German Russian Hindi Arabic Portuguese
















Summary for the public


What is Procoralan?

Procoralan is a medicine that contains the active substance ivabradine. It is available as salmon-coloured tablets (oblong: 5 mg; triangular: 7.5 mg). The 5‑mg tablets have a score line that enables them to be divided into two equal halves, each containing 2.5 mg ivabradine.


What is Procoralan used for?

Procoralan is used to treat the symptoms of long-term stable angina (pains to the chest, jaw and back, brought on by physical effort and due to problems with the blood flow to the heart). It is used in adults (aged 18 years or over) with coronary artery disease (obstruction of the blood vessels that supply the heart) who have a normal sinus rhythm (heartbeat). It can be used in the following groups:

  • patients who cannot take or tolerate beta‑blockers (another type of medicine to treat angina);
  • patients whose disease is not controlled with beta‑blockers and whose heart rate is above 60 beats per minute. Procoralan is used in combination with beta‑blockers in these patients.

The medicine can only be obtained with a prescription.


How is Procoralan used?

Procoralan is taken twice a day with meals, once in the morning and once in the evening.

The recommended starting dose is 5 mg twice a day, although 2.5 mg twice a day can be used in patients over the age of 75 years, before the dose is increased to 5 mg twice a day. After three to four weeks of treatment, the dose may be increased to 7.5 mg twice a day depending on the patient’s response.


How does Procoralan work?

The symptoms of angina are caused by the heart not receiving enough oxygenated blood. In stable angina, these symptoms appear during physical effort. The active substance in Procoralan, ivabradine, works by blocking the ‘If currents’ in the sinus node, the ‘pacemaker’ for the heart that controls the heart’s contractions and regulates the heart rate. When these currents are blocked, the heart rate is lowered, so that the heart has less work to do and needs less oxygenated blood. Procoralan therefore reduces or prevents the symptoms of angina.


How has Procoralan been studied?

Procoralan has been studied in five main studies involving over 4,000 adults with long-term stable angina. The medicine was compared with placebo (a dummy treatment) in 360 patients, atenolol (a beta‑blocker) in 939 patients and amlodipine (another medicine used to treat angina) in 1,195 patients. It was also compared with placebo as an add-on to atenolol in 889 patients and as an add-on to amlodipine in 728 patients. Each study lasted three to four months. The main measure of effectiveness was how long the patients could exercise on a bicycle or a treadmill, measured at the start and the end of each study.


What benefit has Procoralan shown during the studies?

Procoralan was more effective than placebo at improving exercise capacity and was as effective as atenolol and amlodipine. Procoralan was also more effective than placebo when added to atenolol. However, adding Procoralan to amlodipine did not provide an additional benefit.


What is the risk associated with Procoralan?

The most common side effect with Procoralan (seen in more than 1 patient in 10) is luminous phenomena or ‘phosphenes’ (a temporary brightness in the field of vision). For the full list of all side effects reported with Procoralan, see the package leaflet.

Procoralan should not be used in people who may be hypersensitive (allergic) to ivabradine or any of the other ingredients. It must not be used in patients who have a resting heart rate below 60 beats per minute, very low blood pressure, various types of heart disorder (cardiogenic shock, rhythm disorders, heart attack or heart failure) or severe liver problems. It must not be used in women who are pregnant or breast-feeding. For the full list of restrictions, see the package leaflet.

Caution is needed if Procoralan is taken with some other medicines. See the package leaflet for full details.


Why has Procoralan been approved?

The CHMP concluded that Procoralan has sufficient effectiveness against angina and an acceptable safety profile for it to provide an alternative treatment for patients who cannot take beta‑blockers or whose disease is not controlled with them. The Committee decided that Procoralan’s benefits are greater than its risks and recommended that it be given marketing authorisation.


Other information about Procoralan

The European Commission granted a marketing authorisation valid throughout the European Union for Procoralan to Les Laboratoires Servier on 25 October 2005. The marketing authorisation is valid for an unlimited period.

For more information about treatment with Procoralan, read the package leaflet (also part of the EPAR) or contact your doctor or pharmacist.

Authorisation details
Name: Procoralan
EMEA Product number: EMEA/H/C/000597
Active substance: ivabradine
INN or common name: ivabradine
Therapeutic area: Angina Pectoris
ATC Code: C01EB17
Marketing Authorisation Holder: Les Laboratoires Servier
Revision: 6
Date of issue of Market Authorisation valid throughout the European Union: 25/10/2005
Contact address:
Les Laboratoires Servier
22 rue Garnier
92200 Neuilly sur Seine
France



Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


1.
NAME OF THE MEDICINAL PRODUCT
Procoralan 5 mg film-coated tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 5 mg ivabradine (equivalent to 5.390 mg ivabradine as hydrochloride).
Excipient: 63.91 mg lactose monohydrate
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Film-coated tablet.
Salmon-coloured, oblong, film-coated tablet scored on both sides, engraved with “5” on one face
and on the other face.
The tablet can be divided into equal halves.
4.
CLINICAL PARTICULARS
4.1 Therapeutic indications
Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal
sinus rhythm. Ivabradine is indicated :
- in adults 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.
4.2 Posology and method of administration
Posology
For the different doses, film-coated tablets containing 5 mg and 7.5 mg ivabradine are available.
The usual recommended starting dose of ivabradine is 5 mg twice daily. After three to four weeks of
treatment, the dose may be increased to 7.5 mg twice daily depending on the therapeutic response.
If, during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest or the
patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the
dose must be titrated downward including the possible dose of 2.5 mg twice daily (one half 5 mg
tablet twice daily). Treatment must be discontinued if heart rate below 50 bpm or symptoms of
bradycardia persist (see section 4.4).
Special population
Elderly
Since ivabradine has been studied in a limited number of patients aged 75 years or more, a lower
starting dose should be considered for these patients (2.5 mg twice daily i.e. one half 5 mg tablet twice
daily) before up-titration if necessary.
2
Renal impairment
No dose adjustment is required in patients with renal insufficiency and creatinine clearance above
15 ml/min (see section 5.2).
No data are available in patients with creatinine clearance below 15 ml/min. Ivabradine should
therefore be used with precaution in this population.
Hepatic impairment
No dose adjustment is required in patients with mild hepatic impairment. Caution should be exercised
when using ivabradine in patients with moderate hepatic impairment. Ivabradine is contra-indicated
for use in patients with severe hepatic insufficiency, since it has not been studied in this population
and a large increase in systemic exposure is anticipated (see sections 4.3 and 5.2).
Paediatric population
The safety and efficacy of ivabradine in children aged below 18 years have not yet been established.
No data are available.
Method of administration
Tablets must be taken orally twice daily, i.e. once in the morning and once in the evening during meals
(see section 5.2).
4.3 Contraindications
-
Hypersensitivity to the active substance or to any of the excipients (see section 6.1)
-
Resting heart rate below 60 beats per minute prior to treatment
-
Cardiogenic shock
-
Acute myocardial infarction
-
Severe hypotension (< 90/50 mmHg)
-
Severe hepatic insufficiency
-
Sick sinus syndrome
-
Sino-atrial block
-
Heart failure patients with NYHA functional classification III-IV
-
Pacemaker dependent
-
Unstable angina
-
AV-block of 3 rd degree
-
Combination with strong cytochrome P450 3A4 inhibitors such as azole antifungals
(ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os ,
josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see
sections 4.5 and 5.2)
-
Pregnancy, lactation (see section 4.6)
4.4 Special warnings and precautions for use
Special warnings
Cardiac arrhythmias
Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its
efficacy when a tachyarrhythmia occurs (eg. ventricular or supraventricular tachycardia). Ivabradine is
therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere
with sinus node function.
It is recommended to regularly clinically monitor ivabradine treated patients for the occurrence of
atrial fibrillation (sustained or paroxysmal), which should also include ECG monitoring if clinically
indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse).
3
Use in patients with AV-block of 2 nd degree
Ivabradine is not recommended in patients with AV-block of 2 nd degree.
Use in patients with a low heart rate
Ivabradine must not be initiated in patients with a pre-treatment resting heart rate below 60 beats per
minute (see section 4.3).
If, during treatment, resting heart rate decreases persistently below 50 bpm or the patient experiences
symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated
downward or treatment discontinued if heart rate below 50 bpm or symptoms of bradycardia persist
(see section 4.2).
Combination with calcium channel blockers
Concomitant use of ivabradine with heart rate reducing calcium channel blockers such as verapamil or
diltiazem is not recommended (see section 4.5). No safety issue has been raised on the combination of
ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine. Additional
efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been
established (see section 5.1).
Chronic heart failure
Heart failure must be appropriately controlled before considering ivabradine treatment. The use of
ivabradine is contra-indicated in heart failure patients with NYHA functional classification III-IV and
should be used with caution in heart failure patients with NYHA functional classification I-II (see
section 4.3).
Stroke
The use of ivabradine is not recommended immediately after a stroke since no data is available in
these situations.
Visual function
Ivabradine influences on retinal function (see section 5.1). To date, there is no evidence of a toxic
effect of ivabradine on the retina, but the effects of long-term ivabradine treatment beyond one year on
retinal function are currently not known. Cessation of treatment should be considered if any
unexpected deterioration in visual function occurs. Caution should be exercised in patients with
retinitis pigmentosa.
Precautions for use
Patients with hypotension
Limited data are available in patients with mild to moderate hypotension, and ivabradine should
therefore be used with caution in these patients. Ivabradine is contra-indicated in patients with severe
hypotension (blood pressure < 90/50 mmHg) (see section 4.3).
Atrial fibrillation - Cardiac arrhythmias
There is no evidence of risk of (excessive) bradycardia on return to sinus rhythm when
pharmacological cardioversion is initiated in patients treated with ivabradine. However, in the absence
of extensive data, non urgent DC-cardioversion should be considered 24 hours after the last dose of
ivabradine.
Use in patients with congenital QT syndrome or treated with QT prolonging medicinal products
The use of ivabradine in patients with congenital QT syndrome or treated with QT prolonging
medicinal products should be avoided (see section 4.5). If the combination appears necessary, close
cardiac monitoring is needed.
4
Excipients
Since tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Concomitant use not recommended
QT prolonging medicinal products
- Cardiovascular QT prolonging medicinal products (e.g. quinidine, disopyramide, bepridil, sotalol,
ibutilide, amiodarone).
- Non cardiovascular QT prolonging medicinal products (e.g. pimozide, ziprasidone, sertindole,
mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).
The concomitant use of cardiovascular and non cardiovascular QT prolonging medicinal products with
ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the
combination appears necessary, close cardiac monitoring is needed (see section 4.4).
Pharmacokinetic interactions
Cytochrome P450 3A4 (CYP3A4)
Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome.
Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4
substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to
interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant
extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine
plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine
may be associated with the risk of excessive bradycardia (see section 4.4).
Contra-indication of concomitant use
The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole,
itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os , josamycin, telithromycin),
HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contra-indicated (see section 4.3).
The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily)
increased ivabradine mean plasma exposure by 7 to 8 fold.
Concomitant use not recommended
Moderate CYP3A4 inhibitors: specific interaction studies in healthy volunteers and patients have
shown that the combination of ivabradine with the heart rate reducing agents diltiazem or verapamil
resulted in an increase in ivabradine exposure (2 to 3 fold increase in AUC) and an additional heart
rate reduction of 5 bpm. The concomitant use of ivabradine with these medicinal products is not
recommended (see section 4.4).
Concomitant use with precautions
- Moderate CYP3A4 inhibitors: the concomitant use of ivabradine with other moderate CYP3A4
inhibitors (e.g. fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if
resting heart rate is above 60 bpm, with monitoring of heart rate.
- Grapefruit juice: ivabradine exposure was increased by 2-fold following the co-administration with
grapefruit juice. Therefore the intake of grapefruit juice should be restricted during the treatment
with ivabradine.
- CYP3A4 inducers: CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum
perforatum [St John’s Wort]) may decrease ivabradine exposure and activity. The concomitant use
of CYP3A4 inducing medicinal products may require an adjustment of the dose of ivabradine. The
combination of ivabradine 10 mg twice daily with St John’s Wort was shown to reduce ivabradine
5
AUC by half. The intake of St John’s Wort should be restricted during the treatment with
ivabradine.
Other concomitant use
Specific drug-drug interaction studies have shown no clinically significant effect of the following
medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors
(omeprazole, lansoprazole), sildenafil, HMG CoA reductase inhibitors (simvastatin), dihydropyridine
calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition there was no
clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine,
lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the
pharmacodynamics of aspirin.
In pivotal phase III clinical trials the following medicinal products were not restricted and therefore
were routinely combined with ivabradine with no evidence of safety concerns: angiotensin converting
enzyme inhibitors, angiotensin II antagonists, diuretics, short and long acting nitrates, HMG CoA
reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other anti-platelet
medicinal products.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of ivabradine in pregnant women.
Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and
teratogenic effects (see section 5.3). The potential risk for humans is unknown. Therefore, ivabradine
is contra-indicated during pregnancy (see section 4.3).
Breastfeeding
Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contra-indicated
during breast-feeding (see section 4.3).
Fertility
Studies in rats have shown no effect on fertility in males and females (see section 5.3).
4.7 Effects on ability to drive and use machines
A specific study to assess the possible influence of ivabradine on driving performance has been
performed in healthy volunteers where no alteration of the driving performance was evidenced.
Ivabradine has no influence on the ability to drive and use machines. However, ivabradine may cause
transient luminous phenomena consisting mainly of phosphenes (see section 4.8). The possible
occurrence of such luminous phenomena should be taken into account when driving or using machines
in situations where sudden variations in light intensity may occur, especially when driving at night.
4.8 Undesirable effects
Procoralan has been studied in clinical trials involving nearly 5,000 participants. Approximately 2,900
patients have been treated with ivabradine in phase II-III studies.
The most common adverse reactions with ivabradine, luminous phenomena (phosphenes) and
bradycardia, are dose dependent and related to the pharmacological effect of the medicinal product.
The following adverse reactions have been reported during clinical trials and are ranked using the
following frequency: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from
the available data).
6
System Organ Class
Frequency
Preferred Term
Eye disorders
Very common
Luminous phenomena (phosphenes)
Common
Blurred vision
Bradycardia
AV 1 st degree block (ECG prolonged PQ
interval)
Cardiac disorders
Common
Ventricular extrasystoles
Uncommon
Palpitations, supraventricular extrasystoles
Nausea
Constipation
Gastrointestinal disorders
Uncommon
Diarrhoea
Headache, generally during the first month
of treatment
General disorders and
administration site conditions
Common
Dizziness, possibly related to bradycardia
Vertigo
Dyspnoea
Uncommon
Investigations
Uncommon
Muscle cramps
Hyperuricaemia
Eosinophilia
Elevated creatinine in blood
Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient
enhanced brightness in a limited area of the visual field. They are usually triggered by sudden
variations in light intensity. The onset of phosphenes is generally within the first two months of
treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to
moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%)
resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the
treatment in relation with phosphenes.
Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment
initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.
4.9 Overdose
Overdose may lead to severe and prolonged bradycardia (see section 4.8).
Severe bradycardia should be treated symptomatically in a specialised environment. In the event of
bradycardia with poor haemodynamic tolerance, symptomatic treatment including intravenous beta-
stimulating medicinal products such as isoprenaline may be considered. Temporary cardiac electrical
pacing may be instituted if required.
5.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB17.
Mechanism of action
Ivabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac
pacemaker I f current that controls the spontaneous diastolic depolarisation in the sinus node and
regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial,
7
 
atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular
repolarisation.
Ivabradine can interact also with the retinal current I h which closely resembles cardiac I f . It participates
in the temporal resolution of the visual system, by curtailing the retinal response to bright light stimuli.
Under triggering circumstances (e.g. rapid changes in luminosity), partial inhibition of I h by ivabradine
underlies the luminous phenomena that may be occasionally experienced by patients. Luminous
phenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the
visual field (see section 4.8).
Pharmacodynamic effects
The main pharmacodynamic property of ivabradine in humans is a specific dose dependent reduction
in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend
towards a plateau effect which is consistent with a reduced risk of severe bradycardia below 40 bpm
(see section 4.8).
At usual recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise.
This leads to a reduction in cardiac workload and myocardial oxygen consumption. Ivabradine does
not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular
repolarisation:
- in clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular
conduction times or corrected QT intervals;
- in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) between 30
and 45%), ivabradine did not have any deleterious influence on LVEF.
Clinical efficacy and safety
The antianginal and anti-ischaemic efficacy of Procoralan was studied in five double-blind randomised
trials (three versus placebo, and one each versus atenolol and amlodipine). These trials included a total
of 4,111 patients with chronic stable angina pectoris, of whom 2,617 received ivabradine.
Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3 to 4 weeks
of treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over
5 mg twice daily was established in a reference-controlled study versus atenolol: total exercise
duration at trough was increased by about 1 minute after one month of treatment with 5 mg twice daily
and further improved by almost 25 seconds after an additional 3-month period with forced titration to
7.5 mg twice daily. In this study, the antianginal and anti-ischaemic benefits of ivabradine were
confirmed in patients aged 65 years or more. The efficacy of 5 and 7.5 mg twice daily was consistent
across studies on exercise test parameters (total exercise duration, time to limiting angina, time to
angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about
70% in the rate of angina attacks. The twice-daily dosing regimen of ivabradine gave uniform efficacy
over 24 hours.
In a 889-patients randomised placebo-controlled study, ivabradine 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).
In a 725-patients randomised placebo-controlled study, ivabradine did not show additional efficacy on
top of amlodipine at the trough of drug activity (12 hours after oral intake) while an additional efficacy
was shown at peak (3-4 hours after oral intake).
Ivabradine efficacy was fully maintained throughout the 3- or 4-month treatment periods in the
efficacy trials. There was no evidence of pharmacological tolerance (loss of efficacy) developing
during treatment nor of rebound phenomena after abrupt treatment discontinuation. The antianginal
and anti-ischaemic effects of ivabradine were associated with dose-dependent reductions in heart rate
and with a significant decrease in rate pressure product (heart rate x systolic blood pressure) at rest and
8
during exercise. The effects on blood pressure and peripheral vascular resistance were minor and not
clinically significant.
A sustained reduction of heart rate was demonstrated in patients treated with ivabradine for at least
one year (n = 713). No influence on glucose or lipid metabolism was observed.
The antianginal and anti-ischaemic efficacy of ivabradine was preserved in diabetic patients (n = 457)
with a similar safety profile as compared to the overall population.
A large outcome study, BEAUTIFUL, was performed in 10917 patients with coronary artery disease
and left ventricular dysfunction (LVEF<40%) on top of optimal background therapy with 86.9% of
patients receiving beta-blockers. The main efficacy criterion was the composite of cardiovascular
death, hospitalization for acute MI or hospitalization for new onset or worsening heart failure. The
study showed no difference in the rate of the primary composite outcome in the ivabradine group by
comparison to the placebo group (relative risk ivabradine:placebo 1.00, p=0.945).
In a post-hoc subgroup of patients with symptomatic angina at randomisation (n=1507), no safety
signal was identified regarding cardiovascular death, hospitalization for acute MI or heart failure
(ivabradine 12.0% versus placebo 15.5%, p=0.05).
5.2 Pharmacokinetic properties
Under physiological conditions, ivabradine is rapidly released from tablets and is highly water-soluble
(>10 mg/ml). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo . The N-
desmethylated derivative of ivabradine has been identified as the main active metabolite in humans.
Absorption and bioavailability
Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma
level reached in about 1 hour under fasting condition. The absolute bioavailability of the film-coated
tablets is around 40%, due to first-pass effect in the gut and liver.
Food delayed absorption by approximately 1 hour, and increased plasma exposure by 20 to 30 %. The
intake of the tablet during meals is recommended in order to decrease intra-individual variability in
exposure (see section 4.2).
Distribution
Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady-state
is close to 100 l in patients. The maximum plasma concentration following chronic administration at
the recommended dose of 5 mg twice daily is 22 ng/ml (CV=29%). The average plasma concentration
is 10 ng/ml (CV=38%) at steady-state.
Biotransformation
Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P450
3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with
an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also
involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4
induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma
concentrations. Inversely, potent inhibitors and inducers may substantially affect ivabradine plasma
concentrations (see section 4.5).
Elimination
Ivabradine is eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an
effective half-life of 11 hours. The total clearance is about 400 ml/min and the renal clearance is about
70 ml/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4% of an
oral dose is excreted unchanged in urine.
9
Linearity/non linearity
The kinetics of ivabradine is linear over an oral dose range of 0.5 – 24 mg.
Special populations
- Elderly: no pharmacokinetic differences (AUC and Cmax) have been observed between elderly (
65 years) or very elderly patients ( 75 years) and the overall population (see section 4.2).
- Renal insufficiency: the impact of renal impairment (creatinine clearance from 15 to 60 ml/min) on
ivabradine pharmacokinetic is minimal, in relation with the low contribution of renal clearance
(about 20 %) to total elimination for both ivabradine and its main metabolite S 18982 (see section
4.2).
- Hepatic impairment: in patients with mild hepatic impairment (Child Pugh score up to 7) unbound
AUC of ivabradine and the main active metabolite were about 20% higher than in subjects with
normal hepatic function. Data are insufficient to draw conclusions in patients with moderate
hepatic impairment. No data are available in patients with severe hepatic impairment (see sections
4.2 and 4.3).
Pharmacokinetic/pharmacodynamic (PK/PD) relationship
PK/PD relationship analysis has shown that heart rate decreases almost linearly with increasing
ivabradine and S 18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher
doses, the decrease in heart rate is no longer proportional to ivabradine plasma concentrations and
tends to reach a plateau. High exposures to ivabradine that may occur when ivabradine is given in
combination with strong CYP3A4 inhibitors may result in an excessive decrease in heart rate although
this risk is reduced with moderate CYP3A4 inhibitors (see sections 4.3, 4.4 and 4.5).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductive toxicity
studies showed no effect of ivabradine on fertility in male and female rats. When pregnant animals
were treated during organogenesis at exposures close to therapeutic doses, there was a higher
incidence of foetuses with cardiac defects in the rat and a small number of foetuses with ectrodactylia
in the rabbit.
In dogs given ivabradine (doses of 2, 7 or 24 mg/kg/day) for one year, reversible changes in retinal
function were observed but were not associated with any damage to ocular structures. These data are
consistent with the pharmacological effect of ivabradine related to its interaction with
hyperpolarisation-activated I h currents in the retina, which share extensive homology with the cardiac
pacemaker I f current.
Other long-term repeat dose and carcinogenicity studies revealed no clinically relevant changes.
Environmental Risk Assessment (ERA)
The environmental risk assessment of ivabradine has been conducted in accordance to European
guidelines on ERA.
Outcomes of these evaluations support the lack of environmental risk of ivabradine and ivabradine
does not pose a threat to the environment.
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core
Lactose monohydrate
Magnesium stearate (E 470 B)
Maize starch
Maltodextrin
Silica, colloidal anhydrous (E 551)
10
Film-coating
Hypromellose (E 464)
Titanium dioxide (E171)
Macrogol 6000
Glycerol (E 422)
Magnesium stearate (E 470 B)
Yellow iron oxide (E172)
Red iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Aluminium/PVC blister packed in cardboard boxes.
Pack sizes
Calendar packs containing 14, 28, 56, 84, 98, 100 or 112 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
22 rue Garnier
92200 Neuilly sur Seine
France
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/05/316/001-007
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 25/10/2005
Date of latest renewal:
10. DATE OF REVISION OF THE TEXT
11
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
12
1.
NAME OF THE MEDICINAL PRODUCT
Procoralan 7.5 mg film-coated tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 7.5 mg ivabradine (equivalent to 8.085 mg ivabradine as
hydrochloride).
Excipient: 61.215 mg lactose monohydrate
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Film-coated tablet.
Salmon-coloured, triangular, film-coated tablet engraved with “7.5” on one face and
on the other
face.
4.
CLINICAL PARTICULARS
4.1 Therapeutic indications
Symptomatic treatment of chronic stable angina pectoris in coronary artery disease adults with normal
sinus rhythm. Ivabradine is indicated :
- in adults 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.
4.2 Posology and method of administration
Posology
For the different doses, film-coated tablets containing 5 mg and 7.5 mg ivabradine are available.
The usual recommended starting dose of ivabradine is 5 mg twice daily. After three to four weeks of
treatment, the dose may be increased to 7.5 mg twice daily depending on the therapeutic response.
If, during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest or the
patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, the
dose must be titrated downward including the possible dose of 2.5 mg twice daily (one half 5 mg
tablet twice daily). Treatment must be discontinued if heart rate below 50 bpm or symptoms of
bradycardia persist (see section 4.4).
Special population
Elderly
Since ivabradine has been studied in a limited number of patients aged 75 years or more, a lower
starting dose should be considered for these patients (2.5 mg twice daily i.e. one half 5 mg tablet twice
daily) before up-titration if necessary.
Renal impairment
No dose adjustment is required in patients with renal insufficiency and creatinine clearance above
15 ml/min (see section 5.2).
13
No data are available in patients with creatinine clearance below 15 ml/min. Ivabradine should
therefore be used with precaution in this population.
Hepatic impairment
No dose adjustment is required in patients with mild hepatic impairment. Caution should be exercised
when using ivabradine in patients with moderate hepatic impairment. Ivabradine is contra-indicated
for use in patients with severe hepatic insufficiency, since it has not been studied in this population
and a large increase in systemic exposure is anticipated (see sections 4.3 and 5.2).
Paediatric population
The safety and efficacy of ivabradine in children aged below 18 years have not yet been established.
No data are available.
Method of administration
Tablets must be taken orally twice daily, i.e. once in the morning and once in the evening during meals
(see section 5.2).
4.3 Contraindications
-
Hypersensitivity to the active substance or to any of the excipients (see section 6.1)
-
Resting heart rate below 60 beats per minute prior to treatment
-
Cardiogenic shock
-
Acute myocardial infarction
-
Severe hypotension (< 90/50 mmHg)
-
Severe hepatic insufficiency
-
Sick sinus syndrome
-
Sino-atrial block
-
Heart failure patients with NYHA functional classification III-IV
-
Pacemaker dependent
-
Unstable angina
-
AV-block of 3 rd degree
-
Combination with strong cytochrome P450 3A4 inhibitors such as azole antifungals
(ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os ,
josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see
sections 4.5 and 5.2)
-
Pregnancy, lactation (see section 4.6)
4.4 Special warnings and precautions for use
Special warnings
Cardiac arrhythmias
Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its
efficacy when a tachyarrhythmia occurs (eg. ventricular or supraventricular tachycardia). Ivabradine is
therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere
with sinus node function.
It is recommended to regularly clinically monitor ivabradine treated patients for the occurrence of
atrial fibrillation (sustained or paroxysmal), which should also include ECG monitoring if clinically
indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse).
14
Use in patients with AV-block of 2 nd degree
Ivabradine is not recommended in patients with AV-block of 2 nd degree.
Use in patients with a low heart rate
Ivabradine must not be initiated in patients with a pre-treatment resting heart rate below 60 beats per
minute (see section 4.3).
If, during treatment, resting heart rate decreases persistently below 50 bpm or the patient experiences
symptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated
downward or treatment discontinued if heart rate below 50 bpm or symptoms of bradycardia persist
(see section 4.2).
Combination with calcium channel blockers
Concomitant use of ivabradine with heart rate reducing calcium channel blockers such as verapamil or
diltiazem is not recommended (see section 4.5). No safety issue has been raised on the combination of
ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine. Additional
efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been
established (see section 5.1).
Chronic heart failure
Heart failure must be appropriately controlled before considering ivabradine treatment. The use of
ivabradine is contra-indicated in heart failure patients with NYHA functional classification III-IV and
should be used with caution in heart failure patients with NYHA functional classification I-II (see
section 4.3).
Stroke
The use of ivabradine is not recommended immediately after a stroke since no data is available in
these situations.
Visual function
Ivabradine influences on retinal function (see section 5.1). To date, there is no evidence of a toxic
effect of ivabradine on the retina, but the effects of long-term ivabradine treatment beyond one year on
retinal function are currently not known. Cessation of treatment should be considered if any
unexpected deterioration in visual function occurs. Caution should be exercised in patients with
retinitis pigmentosa.
Precautions for use
Patients with hypotension
Limited data are available in patients with mild to moderate hypotension, and ivabradine should
therefore be used with caution in these patients. Ivabradine is contra-indicated in patients with severe
hypotension (blood pressure < 90/50 mmHg) (see section 4.3).
Atrial fibrillation - Cardiac arrhythmias
There is no evidence of risk of (excessive) bradycardia on return to sinus rhythm when
pharmacological cardioversion is initiated in patients treated with ivabradine. However, in the absence
of extensive data, non urgent DC-cardioversion should be considered 24 hours after the last dose of
ivabradine.
Use in patients with congenital QT syndrome or treated with QT prolonging medicinal products
The use of ivabradine in patients with congenital QT syndrome or treated with QT prolonging
medicinal products should be avoided (see section 4.5). If the combination appears necessary, close
cardiac monitoring is needed.
15
Excipients
Since tablets contain lactose, patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Concomitant use not recommended
QT prolonging medicinal products
- Cardiovascular QT prolonging medicinal products (e.g. quinidine, disopyramide, bepridil, sotalol,
ibutilide, amiodarone).
- Non cardiovascular QT prolonging medicinal products (e.g. pimozide, ziprasidone, sertindole,
mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).
The concomitant use of cardiovascular and non cardiovascular QT prolonging medicinal products with
ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the
combination appears necessary, close cardiac monitoring is needed (see section 4.4).
Pharmacokinetic interactions
Cytochrome P450 3A4 (CYP3A4)
Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome.
Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4
substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to
interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant
extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine
plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine
may be associated with the risk of excessive bradycardia (see section 4.4).
Contra-indication of concomitant use
The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole,
itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os , josamycin, telithromycin),
HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contra-indicated (see section 4.3).
The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily)
increased ivabradine mean plasma exposure by 7 to 8 fold.
Concomitant use not recommended
Moderate CYP3A4 inhibitors: specific interaction studies in healthy volunteers and patients have
shown that the combination of ivabradine with the heart rate reducing agents diltiazem or verapamil
resulted in an increase in ivabradine exposure (2 to 3 fold increase in AUC) and an additional heart
rate reduction of 5 bpm. The concomitant use of ivabradine with these medicinal products is not
recommended (see section 4.4).
Concomitant use with precautions
- Moderate CYP3A4 inhibitors: the concomitant use of ivabradine with other moderate CYP3A4
inhibitors (e.g. fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if
resting heart rate is above 60 bpm, with monitoring of heart rate.
- Grapefruit juice: ivabradine exposure was increased by 2-fold following the co-administration with
grapefruit juice. Therefore the intake of grapefruit juice should be restricted during the treatment
with ivabradine.
- CYP3A4 inducers: CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum
perforatum [St John’s Wort]) may decrease ivabradine exposure and activity. The concomitant use
of CYP3A4 inducing medicinal products may require an adjustment of the dose of ivabradine. The
combination of ivabradine 10 mg twice daily with St John’s Wort was shown to reduce ivabradine
16
AUC by half. The intake of St John’s Wort should be restricted during the treatment with
ivabradine.
Other concomitant use
Specific drug-drug interaction studies have shown no clinically significant effect of the following
medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors
(omeprazole, lansoprazole), sildenafil, HMG CoA reductase inhibitors (simvastatin), dihydropyridine
calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition there was no
clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine,
lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the
pharmacodynamics of aspirin.
In pivotal phase III clinical trials the following medicinal products were not restricted and therefore
were routinely combined with ivabradine with no evidence of safety concerns: angiotensin converting
enzyme inhibitors, angiotensin II antagonists, diuretics, short and long acting nitrates, HMG CoA
reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other anti-platelet
medicinal products.
Paediatric population
Interaction studies have only been performed in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no or limited amount of data from the use of ivabradine in pregnant women.
Studies in animals have shown reproductive toxicity. These studies have shown embryotoxic and
teratogenic effects (see section 5.3). The potential risk for humans is unknown. Therefore, ivabradine
is contra-indicated during pregnancy (see section 4.3).
Breastfeeding
Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contra-indicated
during breast-feeding (see section 4.3).
Fertility
Studies in rats have shown no effect on fertility in males and females (see section 5.3).
4.7 Effects on ability to drive and use machines
A specific study to assess the possible influence of ivabradine on driving performance has been
performed in healthy volunteers where no alteration of the driving performance was evidenced.
Ivabradine has no influence on the ability to drive and use machines. However, ivabradine may cause
transient luminous phenomena consisting mainly of phosphenes (see section 4.8). The possible
occurrence of such luminous phenomena should be taken into account when driving or using machines
in situations where sudden variations in light intensity may occur, especially when driving at night.
4.8 Undesirable effects
Procoralan has been studied in clinical trials involving nearly 5,000 participants. Approximately 2,900
patients have been treated with ivabradine in phase II-III studies.
The most common adverse reactions with ivabradine, luminous phenomena (phosphenes) and
bradycardia, are dose dependent and related to the pharmacological effect of the medicinal product.
The following adverse reactions have been reported during clinical trials and are ranked using the
following frequency: very common (≥1/10); common (≥1/100 to, <1/10); uncommon (≥1/1,000 to,
<1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from
the available data).
17
System Organ Class
Frequency
Preferred Term
Eye disorders
Very common
Luminous phenomena (phosphenes)
Common
Blurred vision
Bradycardia
AV 1 st degree block (ECG prolonged PQ
interval)
Cardiac disorders
Common
Ventricular extrasystoles
Uncommon
Palpitations, supraventricular extrasystoles
Nausea
Constipation
Gastrointestinal disorders
Uncommon
Diarrhoea
Headache, generally during the first month
of treatment
General disorders and
administration site conditions
Common
Dizziness, possibly related to bradycardia
Vertigo
Dyspnoea
Uncommon
Investigations
Uncommon
Muscle cramps
Hyperuricaemia
Eosinophilia
Elevated creatinine in blood
Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient
enhanced brightness in a limited area of the visual field. They are usually triggered by sudden
variations in light intensity. The onset of phosphenes is generally within the first two months of
treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to
moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%)
resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the
treatment in relation with phosphenes.
Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment
initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.
4.9 Overdose
Overdose may lead to severe and prolonged bradycardia (see section 4.8).
Severe bradycardia should be treated symptomatically in a specialised environment. In the event of
bradycardia with poor haemodynamic tolerance, symptomatic treatment including intravenous beta-
stimulating medicinal products such as isoprenaline may be considered. Temporary cardiac electrical
pacing may be instituted if required.
5.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB17.
Mechanism of action
Ivabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiac
pacemaker I f current that controls the spontaneous diastolic depolarisation in the sinus node and
regulates heart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial,
18
 
atrioventricular or intraventricular conduction times, nor on myocardial contractility or ventricular
repolarisation.
Ivabradine can interact also with the retinal current I h which closely resembles cardiac I f . It participates
in the temporal resolution of the visual system, by curtailing the retinal response to bright light stimuli.
Under triggering circumstances (e.g. rapid changes in luminosity), partial inhibition of I h by
ivabradine underlies the luminous phenomena that may be occasionally experienced by patients.
Luminous phenomena (phosphenes) are described as a transient enhanced brightness in a limited area
of the visual field (see section 4.8).
Pharmacodynamic effects
The main pharmacodynamic property of ivabradine in humans is a specific dose dependent reduction
in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend
towards a plateau effect which is consistent with a reduced risk of severe bradycardia below 40 bpm
(see section 4.8).
At usual recommended doses, heart rate reduction is approximately 10 bpm at rest and during exercise.
This leads to a reduction in cardiac workload and myocardial oxygen consumption. Ivabradine does
not influence intracardiac conduction, contractility (no negative inotropic effect) or ventricular
repolarisation:
- in clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricular
conduction times or corrected QT intervals;
- in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) between 30
and 45%), ivabradine did not have any deleterious influence on LVEF.
Clinical efficacy and safety
The antianginal and anti-ischaemic efficacy of Procoralan was studied in five double-blind randomised
trials (three versus placebo, and one each versus atenolol and amlodipine). These trials included a total
of 4,111 patients with chronic stable angina pectoris, of whom 2,617 received ivabradine.
Ivabradine 5 mg twice daily was shown to be effective on exercise test parameters within 3 to 4 weeks
of treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over
5 mg twice daily was established in a reference-controlled study versus atenolol: total exercise
duration at trough was increased by about 1 minute after one month of treatment with 5 mg twice daily
and further improved by almost 25 seconds after an additional 3-month period with forced titration to
7.5 mg twice daily. In this study, the antianginal and anti-ischaemic benefits of ivabradine were
confirmed in patients aged 65 years or more. The efficacy of 5 and 7.5 mg twice daily was consistent
across studies on exercise test parameters (total exercise duration, time to limiting angina, time to
angina onset and time to 1 mm ST segment depression) and was associated with a decrease of about
70% in the rate of angina attacks. The twice-daily dosing regimen of ivabradine gave uniform efficacy
over 24 hours.
In a 889-patients randomised placebo-controlled study, ivabradine 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).
In a 725-patients randomised placebo-controlled study, ivabradine did not show additional efficacy on
top of amlodipine at the trough of drug activity (12 hours after oral intake) while an additional efficacy
was shown at peak (3-4 hours after oral intake).
Ivabradine efficacy was fully maintained throughout the 3- or 4-month treatment periods in the
efficacy trials. There was no evidence of pharmacological tolerance (loss of efficacy) developing
during treatment nor of rebound phenomena after abrupt treatment discontinuation. The antianginal
and anti-ischaemic effects of ivabradine were associated with dose-dependent reductions in heart rate
and with a significant decrease in rate pressure product (heart rate x systolic blood pressure) at rest and
19
during exercise. The effects on blood pressure and peripheral vascular resistance were minor and not
clinically significant.
A sustained reduction of heart rate was demonstrated in patients treated with ivabradine for at least
one year (n = 713). No influence on glucose or lipid metabolism was observed.
The antianginal and anti-ischaemic efficacy of ivabradine was preserved in diabetic patients (n = 457)
with a similar safety profile as compared to the overall population.
A large outcome study, BEAUTIFUL, was performed in 10917 patients with coronary artery disease
and left ventricular dysfunction (LVEF<40%) on top of optimal background therapy with 86.9% of
patients receiving beta-blockers. The main efficacy criterion was the composite of cardiovascular
death, hospitalization for acute MI or hospitalization for new onset or worsening heart failure. The
study showed no difference in the rate of the primary composite outcome in the ivabradine group by
comparison to the placebo group (relative risk ivabradine:placebo 1.00, p=0.945).
In a post-hoc subgroup of patients with symptomatic angina at randomisation (n=1507), no safety
signal was identified regarding cardiovascular death, hospitalization for acute MI or heart failure
(ivabradine 12.0% versus placebo 15.5%, p=0.05).
5.2 Pharmacokinetic properties
Under physiological conditions, ivabradine is rapidly released from tablets and is highly water-soluble
(>10 mg/ml). Ivabradine is the S-enantiomer with no bioconversion demonstrated in vivo . The N-
desmethylated derivative of ivabradine has been identified as the main active metabolite in humans.
Absorption and bioavailability
Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma
level reached in about 1 hour under fasting condition. The absolute bioavailability of the film-coated
tablets is around 40%, due to first-pass effect in the gut and liver.
Food delayed absorption by approximately 1 hour, and increased plasma exposure by 20 to 30 %. The
intake of the tablet during meals is recommended in order to decrease intra-individual variability in
exposure (see section 4.2).
Distribution
Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady-state
is close to 100 l in patients. The maximum plasma concentration following chronic administration at
the recommended dose of 5 mg twice daily is 22 ng/ml (CV=29%). The average plasma concentration
is 10 ng/ml (CV=38%) at steady-state.
Biotransformation
Ivabradine is extensively metabolised by the liver and the gut by oxidation through cytochrome P450
3A4 (CYP3A4) only. The major active metabolite is the N-desmethylated derivative (S 18982) with
an exposure about 40% of that of the parent compound. The metabolism of this active metabolite also
involves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4
induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasma
concentrations. Inversely, potent inhibitors and inducers may substantially affect ivabradine plasma
concentrations (see section 4.5).
Elimination
Ivabradine is eliminated with a main half-life of 2 hours (70-75% of the AUC) in plasma and an
effective half-life of 11 hours. The total clearance is about 400 ml/min and the renal clearance is about
70 ml/min. Excretion of metabolites occurs to a similar extent via faeces and urine. About 4% of an
oral dose is excreted unchanged in urine.
20
Linearity/non linearity
The kinetics of ivabradine is linear over an oral dose range of 0.5 – 24 mg.
Special populations
- Elderly: no pharmacokinetic differences (AUC and Cmax) have been observed between elderly (
65 years) or very elderly patients ( 75 years) and the overall population (see section 4.2).
- Renal insufficiency: the impact of renal impairment (creatinine clearance from 15 to 60 ml/min) on
ivabradine pharmacokinetic is minimal, in relation with the low contribution of renal clearance
(about 20 %) to total elimination for both ivabradine and its main metabolite S 18982 (see section
4.2).
- Hepatic impairment: in patients with mild hepatic impairment (Child Pugh score up to 7) unbound
AUC of ivabradine and the main active metabolite were about 20% higher than in subjects with
normal hepatic function. Data are insufficient to draw conclusions in patients with moderate
hepatic impairment. No data are available in patients with severe hepatic impairment (see sections
4.2 and 4.3).
Pharmacokinetic/pharmacodynamic (PK/PD) relationship
PK/PD relationship analysis has shown that heart rate decreases almost linearly with increasing
ivabradine and S 18982 plasma concentrations for doses of up to 15-20 mg twice daily. At higher
doses, the decrease in heart rate is no longer proportional to ivabradine plasma concentrations and
tends to reach a plateau. High exposures to ivabradine that may occur when ivabradine is given in
combination with strong CYP3A4 inhibitors may result in an excessive decrease in heart rate although
this risk is reduced with moderate CYP3A4 inhibitors (see sections 4.3, 4.4 and 4.5).
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductive toxicity
studies showed no effect of ivabradine on fertility in male and female rats. When pregnant animals
were treated during organogenesis at exposures close to therapeutic doses, there was a higher
incidence of foetuses with cardiac defects in the rat and a small number of foetuses with ectrodactylia
in the rabbit.
In dogs given ivabradine (doses of 2, 7 or 24 mg/kg/day) for one year, reversible changes in retinal
function were observed but were not associated with any damage to ocular structures. These data are
consistent with the pharmacological effect of ivabradine related to its interaction with
hyperpolarisation-activated I h currents in the retina, which share extensive homology with the cardiac
pacemaker I f current.
Other long-term repeat dose and carcinogenicity studies revealed no clinically relevant changes.
Environmental Risk Assessment (ERA)
The environmental risk assessment of ivabradine has been conducted in accordance to European
guidelines on ERA.
Outcomes of these evaluations support the lack of environmental risk of ivabradine and ivabradine
does not pose a threat to the environment.
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core
Lactose monohydrate
Magnesium stearate (E 470 B)
Maize starch
Maltodextrin
Silica, colloidal anhydrous (E 551)
21
Film-coating
Hypromellose (E 464)
Titanium dioxide (E171)
Macrogol 6000
Glycerol (E 422)
Magnesium stearate (E 470 B)
Yellow iron oxide (E172)
Red iron oxide (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Aluminium/PVC blister packed in cardboard boxes.
Pack sizes
Calendar packs containing 14, 28, 56, 84, 98, 100 or 112 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
22 rue Garnier
92200 Neuilly sur Seine
France
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/05/316/008-014
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 25/10/2005
Date of latest renewal:
10. DATE OF REVISION OF THE TEXT
22
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu
23
ANNEX II
A. MANUFACTURING
AUTHORISATION
HOLDERS
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
24
A
MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers responsible for batch release
Les Laboratoires Servier Industrie, 905, route de Saran - 45520 Gidy, France
Servier (Ireland) Industries Ltd, Gorey Road – Arklow – Co. Wicklow, Ireland
Przedsiebiorstwo Farmaceutyczne ANPHARM S.A., ul. Annopol 6B – 03-236 Warszawa, Poland
Akmon farmacevtske industrije d.o.o., Industrijska cesta 1J - 1290 Grosuplje – Slovenia
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B
CONDITIONS OF THE MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
THE MARKETING AUTHORISATION HOLDER
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 01 (dated
21/07/2005) presented in Module 1.8.1. of the Marketing Authorisation Application, is in place
and functioning before and whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 01 (dated 21/07/2005) of the Risk
Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation
Application and any subsequent updates of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
• When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
• At the request of the European Medicines Agency
25
ANNEX III
LABELLING AND PACKAGE LEAFLET
26
A. LABELLING
27
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
NAME OF THE MEDICINAL PRODUCT
Procoralan 5 mg film-coated tablets
ivabradine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One film-coated tablet contains 5 mg ivabradine (equivalent to 5.39 mg ivabradine as hydrochloride)
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate.
See package leaflet for the other excipients.
4.
PHARMACEUTICAL FORM AND CONTENTS
14 film-coated tablets
[28 film-coated tablets]
[56 film-coated tablets]
[84 film-coated tablets]
[98 film-coated tablets]
[100 film-coated tablets]
[112 film-coated tablets]
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
28
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
22, rue Garnier
92200 Neuilly-sur-Seine
France
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/05/316/001
[EU/1/05/316/002]
[EU/1/05/316/003]
[EU/1/05/316/004]
[EU/1/05/316/005]
[EU/1/05/316/006]
[EU/1/05/316/007]
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
PROCORALAN 5 mg
29
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
NAME OF THE MEDICINAL PRODUCT
Procoralan 5 mg film-coated tablets
ivabradine
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
Abbreviations for days of the week
MON
TUE
WED
THU
FRI
SAT
SUN
30
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
NAME OF THE MEDICINAL PRODUCT
Procoralan 7.5 mg film-coated tablets
ivabradine
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One film-coated tablet contains 7.5 mg ivabradine (equivalent to 8.085 mg ivabradine as
hydrochloride)
3.
LIST OF EXCIPIENTS
Contains lactose monohydrate.
See package leaflet for the other excipients.
4.
PHARMACEUTICAL FORM AND CONTENTS
14 film-coated tablets
[28 film-coated tablets]
[56 film-coated tablets]
[84 film-coated tablets]
[98 film-coated tablets]
[100 film-coated tablets]
[112 film-coated tablets]
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use.
Oral use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
31
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
22, rue Garnier
92200 Neuilly-sur-Seine
France
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/05/316/008
[EU/1/05/316/009]
[EU/1/05/316/010]
[EU/1/05/316/011]
[EU/1/05/316/012]
[EU/1/05/316/013]
[EU/1/05/316/014]
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
PROCORALAN 7.5 mg
32
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
BLISTER
1.
NAME OF THE MEDICINAL PRODUCT
Procoralan 7.5 mg film-coated tablets
ivabradine
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
Les Laboratoires Servier
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
LOT
5.
OTHER
Abbreviations for days of the week
MON
TUE
WED
THU
FRI
SAT
SUN
33
 
B. PACKAGE LEAFLET
34
PACKAGE LEAFLET: INFORMATION FOR THE USER
Procoralan 5 mg film-coated tablets
Procoralan 7.5 mg film-coated tablets
ivabradine
Read all of this leaflet carefully before you start taking this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice side effects not listed in this leaflet, please
tell your doctor or pharmacist.
In this leaflet :
1.
What Procoralan is and what it is used for
2.
Before you take Procoralan
3.
How to take Procoralan
5
How to store Procoralan
6.
Further information
1.
WHAT PROCORALAN IS AND WHAT IT IS USED FOR
Procoralan (ivabradine) is a heart medicine used to treat stable angina pectoris which causes chest
pain.
It is used in adult patients who do not tolerate or cannot take heart medicines called beta-blockers. It is
also used in combination with beta-blockers in adult patients whose condition is not fully controlled
with a beta-blocker and whose heart rate is too high (over 60 beats per minute).
About stable angina pectoris (usually referred to as “angina”):
Stable angina is a heart disease which happens when the heart does not receive enough oxygen. It
usually appears between 40 and 50 years of age. The most common symptom of angina is chest pain
or discomfort. Angina is more likely to happen when the heart beats faster in situations such as
exercise, emotion, exposure to the cold or after eating. This increase in heart rate can cause the chest
pain in people who suffer from angina.
How does Procoralan work?
Procoralan mainly works by reducing the heart rate by a few beats per minute. This lowers the heart’s
need for oxygen especially in the situations when an angina attack is more likely to happen. In this
way Procoralan helps to control and reduce the number of angina attacks.
2.
BEFORE YOU TAKE PROCORALAN
Do not take Procoralan
- if you are allergic (hypersensitive) to ivabradine or any of the other ingredients of Procoralan (see
“further information” for a list of all ingredients);
- if your resting heart rate before treatment is too slow (below 60 beats per minute);
- if you are suffering from cardiogenic shock (a heart condition treated in hospital);
- if you suffer from a heart rhythm disorder;
- if you are having a heart attack;
- if you suffer from very low blood pressure;
35
-
Keep this leaflet. You may need to read it again.
4.
Possible side effects
- if you suffer from unstable angina (a severe form in which chest pain occurs very frequently and
with or without exertion);
- if you suffer from severe heart failure (when your heart fails to work properly);
- if you have a pacemaker;
- if you suffer from severe liver problems;
- if you are already taking medicines for the treatment of fungal infections (such as ketoconazole,
itraconazole), macrolide antibiotics (such as josamycin, clarithromycin, telithromycin or
erythromycin given orally), medicines to treat HIV infections (such as nelfinavir, ritonavir) or
nefazodone (medicine to treat depression) (see “Taking other medicines”);
- if you are pregnant;
- if you are breast-feeding.
Take special care with Procoralan
- if you suffer from heart rhythm disorders (such as irregular heartbeat, palpitation, increase in chest
pain) or sustained atrial fibrillation (a type of irregular heartbeat),
- if you have symptoms such as tiredness, dizziness or shortness of breath (this could mean that
your heart is slowing down too much),
- if you have had a recent stroke (cerebral attack),
- if you suffer from mild to moderate low blood pressure,
- if you suffer from chronic heart failure (when your heart fails to work properly),
- if you suffer from chronic eye retinal disease,
- if you suffer from moderate liver problems,
- if you suffer from severe renal problems.
If any of the above applies to you, talk straight away to your doctor before or while taking Procoralan.
Children
Procoralan is not intended for use in children and adolescents younger than 18 years.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Make sure to tell your doctor if you are taking any of the following medicines, as a dose adjustment of
Procoralan or monitoring should be required:
- diltiazem, verapamil (used for high blood pressure or angina pectoris)
- fluconazole (an antifungal medicine)
- rifampicin (an antibiotic)
- barbiturates (for difficult sleeping or epilepsy)
- phenytoin (for epilepsy)
- Hypericum perforatum or St John’s Wort (herbal treatment for depression)
- QT prolonging medicines to treat either heart rhythm disorders or other conditions :
- quinidine, disopyramide, ibutilide, sotalol, amiodarone (to treat heart rhythm disorders)
- bepridil (to treat angina pectoris)
- certain types of medicines to treat anxiety, schizophrenia or other psychoses (such as pimozide,
ziprasidone, sertindole)
- anti-malarial medicines (such as mefloquine or halofantrine)
- intravenous erythromycin (an antibiotic)
- pentamidine (an antiparasitic medicine)
- cisapride (against the gastro-oesophageal reflux)
Taking Procoralan with food and drink
Limit your consumption of grapefruit juice during treatment with Procoralan.
Pregnancy and breast-feeding
Do not take Procoralan if you are pregnant or planning a pregnancy (see “Do not take Procoralan”).
If you are pregnant and have taken Procoralan, talk to your doctor.
Do not take Procoralan if you are breast-feeding (see “Do not take Procoralan”).
36
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Procoralan may cause temporary luminous visual phenomena (a temporary brightness in the field of
vision, see “Possible side effects”). If this happens to you, be careful when driving or using machines
at times when there could be sudden changes in light intensity, especially when driving at night.
Important information about some of the ingredients of Procoralan
Procoralan contains lactose. If you have been told by your doctor that you have an intolerance to some
sugars, contact your doctor before taking this medicine.
3.
HOW TO TAKE PROCORALAN
Always take Procoralan exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure. The usual recommended starting dose is one tablet of Procoralan 5 mg
twice daily increasing if necessary to one tablet of Procoralan 7.5 mg twice daily. Your doctor will
decide the right dose for you. The usual dose is one tablet in the morning and one tablet in the
evening. In some cases (e.g. if you are elderly), your doctor may prescribe half the dose i.e., one half
5 mg tablet of Procoralan 5 mg (corresponding to 2.5 mg ivabradine) in the morning and one half 5 mg
tablet in the evening.
Procoralan should be taken during meals.
If you take more Procoralan than you should:
A large dose of Procoralan could make you feel breathless or tired because your heart slows down too
much. If this happens, contact your doctor immediately.
If you forget to take Procoralan:
If you forget to take a dose of Procoralan, take the next dose at the usual time. Do not take a double
dose to make up for the forgotten dose.
The calendar printed on the blister containing the tablets should help you remember when you last
took a tablet of Procoralan.
If you stop taking Procoralan:
As the treatment for angina is usually life-long, you should discuss with your doctor before stopping
this medicinal product.
If you think that the effect of Procoralan is too strong or too weak, talk to your doctor or pharmacist.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Procoralan can cause side effects, although not everybody gets them.
The frequency of possible side effects listed below is defined using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data)
Very common:
Luminous visual phenomena (brief moments of increased brightness, most often caused by sudden
changes in light intensity).
37
Common:
Modification in the heart functioning (the symptoms are a slowing down of the heart rate), abnormal
perception of heartbeat, headache, dizziness and blurred vision.
Uncommon:
Palpitations and cardiac extra beats, feeling sick (nausea), constipation, diarrhoea, spinning sensation
(vertigo), difficulty breathing (dyspnoea), muscle cramps and changes in laboratory parameters : high
blood levels of uric acid, an excess of eosinophils (a type of white blood cell) and elevated creatinine
in blood (a breakdown product of muscle).
If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE PROCORALAN
Keep out of the reach and sight of children.
Do not use Procoralan after the expiry date which is stated on the carton and blister after ‘EXP’. The
expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Procoralan contains
- The active substance is ivabradine (as hydrochloride).
Procoralan 5 mg: one film-coated tablet contains 5 mg ivabradine (equivalent to 5.390 mg
ivabradine as hydrochloride).
Procoralan 7.5 mg: one film-coated tablet contains 7.5 mg ivabradine (equivalent to 8.085 mg
ivabradine as hydrochloride).
- The other ingredients in the tablet core are: lactose monohydrate, magnesium stearate (E 470 B),
maize starch, maltodextrin, colloidal anhydrous silica (E 551), and in the tablet coating:
hypromellose (E 464), titanium dioxide (E 171), macrogol 6000, glycerol (E 422), magnesium
stearate (E 470 B), yellow iron oxide (E 172), red iron oxide (E 172).
What Procoralan looks like and contents of the pack
Procoralan 5 mg tablets are salmon-coloured, oblong film-coated tablets scored on both sides,
engraved with “5” on one face and on the other.
Procoralan 7.5 mg tablets are salmon-coloured, triangular, film-coated tablets engraved with “7.5” on
one face and
on the other.
The tablets are available in calendar packs (Aluminium/PVC blisters) of 14, 28, 56, 84, 98, 100 or 112
tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer :
Marketing Authorisation Holder:
Les Laboratoires Servier
22 rue Garnier
38
92200 Neuilly sur Seine - France
Manufacturer:
Les Laboratoires Servier Industrie
905 route de Saran
45520 Gidy – France
Servier (Ireland) Industries Ltd
Gorey Road
Arklow - Co. Wicklow – Ireland
Przedsiebiorstwo Farmaceutyczne ANPHARM S.A.
ul. Annopol 6B – 03-236 Warszawa – Poland
Akmon farmacevtske industrije d.o.o.
Industrijska cesta 1J
1290 Grosuplje – Slovenia
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder.
België/Belgique/Belgien
S.A. Servier Benelux N.V.
Tél/Tel: +32 (0)2 529 43 11
Luxembourg/Luxemburg
S.A. Servier Benelux N.V.
Tél/Tel: +32 (0)2 529 43 11
България
Сервие Медикал ЕООД
Тел.: +359 2 921 57 00
Magyarország
Servier Hungaria Kft.
Tel.: + 36 1 238 77 99
Česká republika
Servier s.r.o.
Tel: +420 222 118 111
Malta
GALEPHARMA Ltd
Tel: +(356) 21 247 082
Danmark
Servier Danmark A/S
Tlf: +45 36 44 22 60
Nederland
Servier Nederland Farma B.V.
Tel: +31 (0)71 5246700
Deutschland
Servier Deutschland GmbH
Tel: +49 (0)89 57095 01
Norge
Servier Danmark A/S
Tlf: +45 36 44 22 60
Eesti
CentralPharma Communications OÜ
Tel: +372 640 00 07
Österreich
Servier Austria GmbH
Tel: +43 (1) 524 39 99
Ελλάδα
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ
Τηλ: +30 210 939 1000
Polska
Servier Polska SP. Z O.O.
Tel.: + 48 (0) 22 594 90 00
España
Laboratorios Servier S.L .
Tel: +34 91 748 96 30
Portugal
Servier Portugal, Lda
Tel: +351 21 312 20 00
France
Les Laboratoires Servier
Tél: +33 (0)1 55 72 60 00
România
Servier Pharma SRL
Tel: +4 021 528 52 80
39
Ireland
Servier Laboratories (Ireland) Ltd.
Tel: +353 (0)1 6638110
Slovenija
Servier Pharma d.o.o.
Tel: +386 (0)1563 48 11
Ísland
Servier Laboratories
c/o Icepharma hf
Sími: +354 540 8000
Slovenská republika
Servier Slovensko spol. s r.o.
Tel: +421 0(2) 5920 41 11
Italia
Servier Italia S.p.A.
Tel: +39 (06) 669081
Suomi/Finland
Servier Finland Oy
Puh/Tel: +358 (0)9 279 80 80
Κύπρος
Χ.Α.Παπαέλληνας & Σία Λτδ
Τηλ: +357 22741741
Sverige
Servier Sverige AB
Tel: +46 (8)5 225 08 00
Latvija
SIA Servier
Latvia
Tel: + 371 67502039
United Kingdom
Servier Laboratories Ltd
Tel: +44 (0)1 753 666409
Lietuva
UAB ”SERVIER PHARMA”
Tel: +370 (5) 2 63 86 28
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
40


Source: European Medicines Agency



- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.



http://www.theodora.com/drugs/eu/procoralan.html

Copyright © 1995-2011 ITA all rights reserved.