Ivabradine Zentiva

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Ivabradine Zentiva 5 mg film-coated tablets 
Ivabradine Zentiva 7.5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Ivabradine Zentiva 5 mg film-coated tablets: 
One film-coated tablet contains 5 mg ivabradine (as hydrochloride). 
 
Ivabradine Zentiva 7.5 mg film-coated tablets: 
One film-coated tablet contains 7.5 mg ivabradine (hydrochloride). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 
Ivabradine Zentiva 5 mg film-coated tablets: 
Oblong, one side and both edges scored white tablets with dimensions 4.8×8.8 mm. The tablet can 
be divided into equal doses. 
 
Ivabradine Zentiva 7.5 mg film-coated tablets: 
White to off white, round tablet with diameter 7.1 mm. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Symptomatic treatment of chronic stable angina pectoris 
Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery 
disease adults with normal sinus rhythm and heart rate ≥ 70 bpm. 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. 
 
Treatment of chronic heart failure 
Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in patients 
in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy including beta-
blocker therapy or when beta-blocker therapy is contraindicated or not tolerated (see section 5.1). 
 



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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. 
 
Symptomatic treatment of chronic stable angina pectoris 
It is recommended that the decision to initiate or titrate treatment takes place with the availability of serial 
heart rate measurements, ECG or ambulatory 24-hour monitoring. 
The starting dose of ivabradine should not exceed 5 mg twice daily in patients aged below 75 years. 
After three to four weeks of treatment, if the patient is still symptomatic, if the initial dose is well tolerated 
and if resting heart rate remains above 60 bpm, the dose may be increased to the next higher dose 
in patients receiving 2.5 mg twice daily or 5 mg twice daily. 
The maintenance dose should not exceed 7.5 mg twice daily. 
If there is no improvement in symptoms of angina within 3 months after start of treatment, treatment 
of ivabradine should be discontinued. 
In addition, discontinuation of treatment should be considered if there is only limited symptomatic 
response and when there is no clinically relevant reduction in resting heart rate within three months. 
If, during treatment, heart rate decreases 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 lowest dose of 2.5 mg twice daily (one half 5 mg tablet twice daily). 
After dose reduction, heart rate should be monitored (see section 4.4). Treatment must be discontinued 
if heart rate remains below 50 bpm or symptoms of bradycardia persist despite dose reduction. 
 
Treatment of chronic heart failure 
The treatment has to be initiated only in patient with stable heart failure. 
It is recommended that the treating physician should be experienced in the management of chronic heart 
failure. 
The usual recommended starting dose of ivabradine is 5 mg twice daily. After two weeks of treatment, 
the dose can be increased to 7.5 mg twice daily if resting heart rate is persistently above 60 bpm 
or decreased to 2.5 mg twice daily (one half 5 mg tablet twice daily) if resting heart rate is persistently 
below 50 bpm or in case of symptoms related to bradycardia such as dizziness, fatigue or hypotension. 
If heart rate is between 50 and 60 bpm, the dose of 5 mg twice daily should be maintained. 
If during treatment, heart rate decreases persistently below 50 beats per minute (bpm) at rest 
or the patient experiences symptoms related to bradycardia, the dose must be titrated downward 
to the next lower dose in patients receiving 7.5 mg twice daily or 5 mg twice daily. If heart rate increases 
persistently above 60 beats per minute at rest, the dose can be up titrated to the next upper dose 
in patients receiving 2.5 mg twice daily or 5 mg twice daily. 
Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist 
(see section 4.4). 
 
Special populations 
Elderly 
In patients aged 75 years or more, a lower starting dose should be considered (2.5 mg twice daily i.e. one 
half 5 mg tablet twice daily) before up-titration if necessary. 
 



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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 for the treatment of chronic heart failure in children aged below 
18 years have not been established. 
Available data are described in sections 5.1 and 5.2 but no recommendation on a posology can 
be made. 
 
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 listed in section 6.1. 
‒ Resting heart rate below 70 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. 
‒ Unstable or acute heart failure. 
‒ Pacemaker dependent (heart rate imposed exclusively by the pacemaker). 
‒ Unstable angina. 
‒ AV-block of 3rd 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). 

‒ Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate 
reducing properties (see section 4.5).  

‒ Pregnancy, lactation and women of child-bearing potential not using appropriate contraceptive 
measures (see section 4.6). 

 



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4.4 Special warnings and precautions for use 
 
Special warnings 
Lack of benefit on clinical outcomes in patients with symptomatic chronic stable angina pectoris 
Ivabradine is indicated only for symptomatic treatment of chronic stable angina pectoris because 
ivabradine has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death) 
(see section 5.1). 
 
Measurement of heart rate 
Given that the heart rate may fluctuate considerably over time, serial heart rate measurements, ECG 
or ambulatory 24-hour monitoring should be considered when determining resting heart rate before 
initiation of ivabradine treatment and in patients on treatment with ivabradine when titration is considered. 
This also applies to patients with a low heart rate, in particular when heart rate decreases below 50 bpm, 
or after dose reduction (see section 4.2). 
 
Cardiac arrhythmias 
Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its 
efficacy when a tachyarrhythmia occurs (e.g. ventricular or supraventricular tachycardia). Ivabradine 
is therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere 
with sinus node function. 
In patients treated with ivabradine the risk of developing atrial fibrillation is increased (see section 4.8). 
Atrial fibrillation has been more common in patients using concomitantly amiodarone or potent class I 
anti-arrhythmics. 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). 
Patients should be informed of signs and symptoms of atrial fibrillation and be advised to contact their 
physician if these occur. 
If atrial fibrillation develops during treatment, the balance of benefits and risks of continued ivabradine 
treatment should be carefully reconsidered. 
Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundle 
branch block right) and ventricular dyssynchrony should be monitored closely. 
 
Use in patients with AV-block of 2nd degree 
Ivabradine is not recommended in patients with AV-block of 2nd degree. 
 
Use in patients with a low heart rate 
Ivabradine must not be initiated in patients with a pre-treatment resting heart rate below 70 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 contraindicated (see sections 4.3 and 4.5). No safety issue has been raised 
on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such 



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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 stable before considering ivabradine treatment. Ivabradine should be used with 
caution in heart failure patients with NYHA functional classification IV due to limited amount of data 
in this population. 
 
Stroke 
The use of ivabradine is not recommended immediately after a stroke since no data is available in these 
situations. 
 
Visual function 
Ivabradine influences retinal function. There is no evidence of a toxic effect of  long-term ivabradine 
treatment on the retina (see section 5.1). 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. 
Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give rise 
to severe arrhythmias, in particular Torsade de pointes. 
 
Hypertensive patients requiring blood pressure treatment modifications 
In the SHIFT trial more patients experienced episodes of increased blood pressure while treated with 
ivabradine (7.1%) compared to patients treated with placebo (6.1%). These episodes occurred most 
frequently shortly after blood pressure treatment was modified, were transient, and did not affect 
the treatment effect of ivabradine. When treatment modifications are made in chronic heart failure patients 
treated with ivabradine blood pressure should be monitored at an appropriate interval (see section 4.8). 
 
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). 



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‒ 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). 
 
Concomitant use with precaution 
Potassium-depleting diuretics (thiazide diuretics and loop diuretics) 
Hypokalaemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting 
combination of hypokalaemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, 
especially in patients with long QT syndrome, whether congenital or substance-induced. 
 
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. 
 
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 contraindicated (see section 
4.3). 
 
Concomitant use not recommended 
Grapefruit juice: ivabradine exposure was increased by 2-fold following the co-administration with 
grapefruit juice. Therefore the intake of grapefruit juice should be avoided. 
 
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 70 bpm, with monitoring of heart rate. 

‒ 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 



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ivabradine 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 routinely combined 
with ivabradine with no evidence of safety concerns: angiotensin converting enzyme inhibitors, 
angiotensin II antagonists, beta-blockers, diuretics, anti-aldosterone agents, 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 
 
Women of childbearing potential 
Women of child-bearing potential should use appropriate contraceptive measures during treatment 
(see section 4.3). 
 
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). 
 
Breast-feeding 
Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contra-indicated 
during breast-feeding (see section 4.3). Women that need treatment with ivabradine should stop breast-
feeding, and choose for another way of feeding their child. 
 
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. However, in post-
marketing experience, cases of impaired driving ability due to visual symptoms have been reported. 
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. 



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Ivabradine has no influence on the ability to use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
Ivabradine has been studied in clinical trials involving nearly 45,000 participants. 
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. 
 
Tabulated list of adverse reactions 
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). 
 

System Organ Class Frequency Preferred Term 
Blood and lymphatic system disorders Uncommon Eosinophilia 
Metabolism and nutrition disorders Uncommon Hyperuricaemia 
Nervous system disorders Common Headache, generally during the first month 

of treatment 
Dizziness, possibly related to bradycardia 

Uncommon* Syncope, possibly related to bradycardia 
Eye disorders Very common Luminous phenomena (phosphenes) 

Common Blurred vision 
Uncommon* Diplopia 

Visual impairment 
Ear and labyrinth disorders Uncommon Vertigo 
Cardiac disorders Common Bradycardia 

AV 1st degree block (ECG prolonged PQ 
interval) 
Ventricular extrasystoles 
Atrial fibrillation 

Uncommon Palpitations 
Supraventricular extrasystoles 

Very rare AV 2nd and 3rd degree block 
Sick sinus syndrome 

Vascular disorders Common Uncontrolled blood pressure 
Uncommon* Hypotension, possibly related to bradycardia 

Respiratory, thoracic and mediastinal 
disorders 

Uncommon Dyspnoea 

Gastrointestinal disorders Uncommon Nausea 
Constipation 
Diarrhoea 
Abdominal pain* 



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System Organ Class Frequency Preferred Term 
Skin and subcutaneous tissue 
disorders 

Uncommon* Angioedema 
Rash 

Rare* Erythema 
Pruritus 
Urticaria 

Musculoskeletal and connective tissue 
disorders 

Uncommon Muscle cramps 

General disorders and administration 
site conditions 

Uncommon* Asthenia, possibly related to bradycardia 
Fatigue, possibly related to bradycardia 

Rare* Malaise, possibly related to bradycardia 
Investigations Uncommon Elevated creatinine in blood 

ECG prolonged QT interval 
* Frequency calculated from clinical trials for adverse events detected from spontaneous report. 
 
Description of selected adverse reactions 
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. Phosphenes may also be described as a halo, image decomposition (stroboscopic 
or kaleidoscopic effects), coloured bright lights, or multiple image (retinal persistency). 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. 
 
In the SIGNIFY study atrial fibrillation was observed in 5.3% of patients taking ivabradine compared 
to 3.8% in the placebo group. In a pooled analysis of all the Phase II/III double blind controlled clinical 
trials with a duration of at least 3 months including more than 40,000 patients, the incidence of atrial 
fibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, corresponding 
to a hazard ratio of 1.26, 95% CI [1.15 – 1.39]. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
Overdose may lead to severe and prolonged bradycardia (see section 4.8). 
 
Management 
Severe bradycardia should be treated symptomatically in a specialised environment. In the event 
of bradycardia with poor haemodynamic tolerance, symptomatic treatment including intravenous beta-

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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 If 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, atrioventricular 
or intraventricular conduction times, nor on myocardial contractility or ventricular repolarisation. 
 
Ivabradine can interact also with the retinal current Ih which closely resembles cardiac If. 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 Ih 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 ivabradine 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 



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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 10 mg o.d. 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). 
 
In a 1,277-patients randomised placebo-controlled study, ivabradine demonstrated a statistically 
significant additional efficacy on response to treatment (defined as a decrease of at least 3 angina 
attacks per week and/or an increase in the time to 1 mm ST segment depression of at least 60 s during 
a treadmill ETT) on top of amlodipine 5 mg o.d. or nifedipine GITS 30 mg o.d. at the trough of drug 
activity (12 hours after oral ivabradine intake) over a 6-week treatment period (OR = 1.3, 95% CI [1.0 
– 1.7]; p = 0.012). Ivabradine did not show additional efficacy on secondary endpoints of ETT 
parameters at the trough of drug activity while an additional efficacy was shown at peak (3 – 4 hours 
after oral ivabradine 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 × systolic blood pressure) at rest and 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 10,917 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 = 1,507), 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). 
 
A large outcome study, SIGNIFY, was performed in 19,102 patients with coronary artery disease and 
without clinical heart failure (LVEF > 40%), on top of optimal background therapy. A therapeutic scheme 
higher than the approved posology was used (starting dose 7.5 mg b.i.d. (5 mg b.i.d., if age ≥ 75 years) 



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and titration up to 10 mg b.i.d.). The main efficacy criterion was the composite of cardiovascular death 
or non-fatal MI. The study showed no difference in the rate of the primary composite endpoint (PCE) 
in the ivabradine group by comparison to the placebo group (relative risk ivabradine/placebo 1.08, p = 
0.197). Bradycardia was reported by 17.9 % of patients in the ivabradine group (2.1% in the placebo 
group). Verapamil, diltiazem or strong CYP 3A4 inhibitors were received by 7.1% of patients during 
the study. 
 
A small statistically significant increase in the PCE was observed in a pre-specified subgroup of patients 
with angina patients in CCS class II or higher at baseline (n = 12,049) (annual rates 3.4% versus 2.9%, 
relative risk ivabradine/placebo 1.18, p = 0.018), but not in the subgroup of the overall angina population 
in CCS class ≥ I (n = 14,286) (relative risk ivabradine/placebo 1.11, p = 0.110). 
 
The higher than approved dose used in the study did not fully explain these findings. 
 
The SHIFT study was a large multicentre, international, randomised double-blind placebo controlled 
outcome trial conducted in 6,505 adult patients with stable chronic CHF (for ≥ 4 weeks), NYHA class II 
to IV, with a reduced left ventricular ejection fraction (LVEF ≤ 35%) and a resting heart rate ≥ 70 bpm. 
Patients received standard care including beta-blockers (89%), ACE inhibitors and/or angiotensin II 
antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). In the ivabradine group, 67% 
of patients were treated with 7.5 mg twice a day. The median follow-up duration was 22.9 months. 
Treatment with ivabradine was associated with an average reduction in heart rate of 15 bpm 
from a baseline value of 80 bpm. The difference in heart rate between ivabradine and placebo arms was 
10.8 bpm at 28 days, 9.1 bpm at 12 months and 8.3 bpm at 24 months. 
The study demonstrated a clinically and statistically significant relative risk reduction of 18% in the rate 
of the primary composite endpoint of cardiovascular mortality and hospitalisation for worsening heart 
failure (hazard ratio: 0.82, 95% CI [0.75; 0.90], p < 0.0001) apparent within 3 months of initiation of 
treatment. The absolute risk reduction was 4.2%. The results on the primary endpoint are mainly driven by 
the heart failure endpoints, hospitalisation for worsening heart failure (absolute risk reduced by 4.7%) 
and deaths from heart failure (absolute risk reduced by 1.1%). 
 
Treatment effect on the primary composite endpoint, its components and secondary endpoints 

 Ivabradine 
(N = 3,241) 
n (%) 

Placebo 
(N = 3,264) 
n (%) 

Hazard Ratio 
[95% CI] 

p-value 

Primary composite endpoint 793 (24.47) 937 (28.71) 0.82 [0.75; 0.90] < 0.0001 
Components of the composite: 
‒ CV death 
‒ Hospitalisation for worsening HF 

 
449 (13.85) 
514 (15.86) 

 
491 (15.04) 
672 (20.59) 

 
0.91 [0.80; 1.03] 
0.74 [0.66; 0.83] 

 
0.128 
< 0.0001 

Other secondary endpoints     
‒ All cause death 
‒ Death from HF 
‒ Hospitalisation for any cause 
‒ Hospitalisation for CV reason 

503 (15.52) 
113 (3.49) 
1,231 (37.98) 
977 (30.15) 

552 (16.91) 
151 (4.63) 
1,356 (41.54) 
1,122 (34.38) 

0.90 [0.80; 1.02] 
0.74 [0.58;0.94] 
0.89 [0.82;0.96] 
0.85 [0.78; 0.92] 

0.092 
0.014 
0.003 
0.0002 

 
The reduction in the primary endpoint was observed consistently irrespective of gender, NYHA class, 
ischaemic or non-ischaemic heart failure aetiology and of background history of diabetes or hypertension. 
 



14 

 

In the subgroup of patients with HR ≥ 75 bpm (n = 4,150), a greater reduction was observed 
in the primary composite endpoint of 24% (hazard ratio: 0.76, 95% CI [0.68; 0.85], p < 0.0001) 
and for other secondary endpoints, including all cause death (hazard ratio: 0.83, 95% CI [0.72; 0.96], 
p = 0.0109) and CV death (hazard ratio: 0.83, 95% CI [0.71; 0.97], p = 0.0166). In this subgroup 
of patients, the safety profile of ivabradine is in line with the one of the overall population. 
 
A significant effect was observed on the primary composite endpoint in the overall group of patients 
receiving beta-blocker therapy (hazard ratio: 0.85, 95% CI [0.76; 0.94]). In the subgroup of patients with 
HR ≥ 75 bpm and on the recommended target dose of beta-blocker, no statistically significant benefit was 
observed on the primary composite endpoint (hazard ratio: 0.97, 95% CI [0.74; 1.28]) and other secondary 
endpoints, including hospitalisation for worsening heart failure (hazard ratio: 0.79, 95% CI [0.56; 1.10]) 
or death from heart failure (hazard ratio: 0.69, 95% CI [0.31; 1.53]). 
 
There was a significant improvement in NYHA class at last recorded value, 887 (28%) of patients 
on ivabradine improved versus 776 (24%) of patients on placebo (p = 0.001). 
 
In a 97-patient  randomised placebo-controlled study, the data collected during specific ophthalmologic 
investigations, aiming at documenting the function of the cone and rod systems and the ascending visual 
pathway (i.e. electroretinogram, static and kinetic visual fields, colour vision, visual acuity), in patients 
treated with ivabradine for chronic stable angina pectoris over 3 years, did not show any retinal toxicity. 
 
Paediatric population 
A randomised, double blind, placebo controlled study was performed in 116 paediatric patients 
(17 aged [6 – 12] months, 36 aged [1 – 3] years and 63 aged [3 – 18] years) with CHF and dilated 
cardiomyopathy (DCM) on top of optimal background treatment. 74 received ivabradine (ratio 2:1). 
The starting dose was 0.02 mg/kg b.i.d. in age-subset [6 – 12] months, 0.05 mg/kg b.i.d. in [1 – 3] years 
and [3 – 18] years < 40 kg, and 2.5 mg b.i.d. in [3 – 18] years and ≥ 40 kg. The dose was adapted 
depending on the therapeutic response with maximum doses of 0.2 mg/kg b.i.d., 0.3 mg/kg b.i.d. and 
15 mg b.i.d., respectively. In this study, ivabradine was administered as oral liquid formulation or tablet 
twice daily. The absence of pharmacokinetic difference between the 2 formulations was shown 
in an open-label randomised two-period cross-over study in 24 adult healthy volunteers. 
A 20% heart rate reduction, without bradycardia, was achieved by 69.9% of patients in the ivabradine 
group versus 12.2% in the placebo group during the titration period of 2 to 8 weeks (Odds Ratio: E = 
17.24, 95% CI [5.91 ; 50.30]). 
The mean ivabradine doses allowing to achieve a 20% HRR were 0.13±0.04 mg/kg b.i.d., 0.10±0.04 
mg/kg b.i.d. and 4.1±2.2 mg b.i.d. in the age subsets [1 – 3] years, [3 – 18] years and < 40 kg and 
[3 – 18] years and ≥ 40 kg, respectively. 
Mean LVEF increased from 31.8% to 45.3% at M012 in ivabradine group versus 35.4% to 42.3% 
in the placebo group. There was an improvement in NYHA class in 37.7% of ivabradine patients 
versus 25.0% in the placebo group. These improvements were not statistically significant. 
The safety profile, over one year, was similar to the one described in adult CHF patients. 
 
The long-term effects of ivabradine on growth, puberty and general development as well as the long- 
term efficacy of therapy with ivabradine in childhood to reduce cardiovascular morbidity and mortality 
have not been studied. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
ivabradine in all subsets of the paediatric population for the treatment of angina pectoris. 



15 

 

The European Medicines Agency has waived the obligation to submit the results of studies with 
ivabradine in children aged 0 to less than 6 months for the treatment of chronic heart failure. 
 
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 P4503A4 
(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. 
 
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 impairment 



16 

 

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). 
 
Paediatric population 
The pharmacokinetic profile of ivabradine in paediatric chronic heart failure patients aged 6 months 
to less than 18 years is similar to the pharmacokinetics described in adults when a titration scheme based 
on age and weight is applied. 
 
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). 
The PK/PD relationship of ivabradine in paediatric chronic heart failure patients aged 6 months to less 
than 18 years is similar to the PK/PD relationship described in adults. 
 
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 Ih currents in the retina, which share extensive homology with the cardiac pacemaker If 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. 
 
 



17 

 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Core: 
Mannitol 
Crospovidone 
Magnesium stearate 
 
Film-coating: 
Hypromellose 
Titanium dioxide 
Macrogol 400 
Glycerol 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years. 
 
6.4 Special precautions for storage 
 
Store below 25 °C.  
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
OPA/Alu/PVC-Alu blisters, paper carton. 
Pack size: 
Ivabradine Zentiva 5 mg film-coated tablets: 14, 28, 56, 84, 98, 100, 112 film-coated tablets 
Ivabradine Zentiva 7.5 mg: 14, 28, 56, 84, 98, 100, 112 film-coated tablets 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 



18 

 

7. MARKETING AUTHORISATION HOLDER 
 
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Ivabradine Zentiva 5 mg film-coated tablets: 
EU/1/16/1144/001 
EU/1/16/1144/002 
EU/1/16/1144/003 
EU/1/16/1144/004 
EU/1/16/1144/005 
EU/1/16/1144/006 
EU/1/16/1144/007 
 
Ivabradine Zentiva 7.5 mg film-coated tablets: 
EU/1/16/1144/008 
EU/1/16/1144/009 
EU/1/16/1144/010 
EU/1/16/1144/011 
EU/1/16/1144/012 
EU/1/16/1144/013 
EU/1/16/1144/014 
 
 
9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 11/11/2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

  

http://www.ema.europa.eu/


19 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



20 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 

 
Zentiva, k.s. 
U Kabelovny 130 
Dolni Měcholupy 
102 37 Prague 10 
Czech Republic 
 
S.C. Zentiva S.A 
50 Theodor Pallady Blvd, 
District 3, 
032266 Bucharest 
Romania 
 
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 OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
Medicinal product subject to medical prescription. 

 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

 
• Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are 
set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-
portal. 
 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 
USE OF THE MEDICINAL PRODUCT 

 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed 
subsequent updates of the RMP. 
An updated RMP should be submitted: 



21 

 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

  



22 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



23 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



24 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ivabradine Zentiva 5 mg film-coated tablets 
Ivabradine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One film-coated tablet contains 5 mg ivabradine (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
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 OF ADMINISTRATION 
 
Oral use 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 



25 

 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 25 °C. Store in the original package in order to protect from moisture. 
 
 
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 
 
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1144/001 
EU/1/16/1144/002 
EU/1/16/1144/003 
EU/1/16/1144/004 
EU/1/16/1144/005 
EU/1/16/1144/006 
EU/1/16/1144/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Ivabradine Zentiva 5 mg 



26 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



27 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ivabradine Zentiva 5 mg film-coated tablets 
Ivabradine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
MON [sun] MON [moon] 
TUE [sun] TUE [moon] 
WED [sun] WED [moon] 
THU [sun] THU [moon] 
FRI [sun] FRI [moon] 
SAT [sun] SAT [moon] 
SUN [sun] SUN [moon] 



28 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Ivabradine Zentiva 7.5 mg film-coated tablets 
Ivabradine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 
 
One film-coated tablet contains 7.5 mg ivabradine (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
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 OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED 
OUT OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 



29 

 

8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store below 25 °C. Store in the original package in order to protect from moisture. 
 
 
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 
 
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/16/1144/008 
EU/1/16/1144/009 
EU/1/16/1144/010 
EU/1/16/1144/011 
EU/1/16/1144/012 
EU/1/16/1144/013 
EU/1/16/1144/014 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Ivabradine Zentiva 7.5 mg 



30 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 
 



31 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Ivabradine Zentiva 7.5 mg film-coated tablets 
Ivabradine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Zentiva logo 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
MON [sun] MON [moon] 
TUE [sun] TUE [moon] 
WED [sun] WED [moon] 
THU [sun] THU [moon] 
FRI [sun] FRI [moon] 
SAT [sun] SAT [moon] 
SUN [sun] SUN [moon] 
  



32 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



33 

 

Package leaflet: Information for the patient 
 

Ivabradine Zentiva 5 mg film-coated tablets 
Ivabradine Zentiva 7.5 mg film-coated tablets 

 
Ivabradine 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 

‒ Keep this leaflet. You may need to read it again. 
‒ If you have any further questions, ask your doctor or pharmacist. 
‒ This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even 

if their signs of illness are the same as yours. 
‒ If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Ivabradine Zentiva is and what it is used for 
2. What you need to know before you take Ivabradine Zentiva 
3. How to take Ivabradine Zentiva 
4. Possible side effects 
5. How to store Ivabradine Zentiva 
6. Contents of the pack and other information 
 
 
1. What Ivabradine Zentiva is and what it is used for 
 
Ivabradine Zentiva (ivabradine) is a heart medicine used to treat: 

‒ Symptomatic stable angina pectoris (which causes chest pain) in adult patients whose heart rate 
is over or equal to 70 beats per minute. 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. 

‒ Chronic heart failure in adult patients whose heart rate is over or equal to 75 beats per minute. 
It is used in combination with standard therapy, including beta-blocker therapy or when beta-blockers 
are contraindicated or not tolerated. 

 
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. 
 



34 

 

About chronic heart failure 
Chronic heart failure is a heart disease which happens when your heart cannot pump enough blood 
to the rest of your body. The most common symptoms of heart failure are breathlessness, fatigue, tiredness 
and ankle swelling. 
 
How does Ivabradine Zentiva work? 
Ivabradine Zentiva mainly works by reducing the heart rate by a few beats per minute. This lowers 
the heartʼs need for oxygen especially in the situations when an angina attack is more likely to happen. 
In this way Ivabradine Zentiva helps to control and reduce the number of angina attacks. 
Furthermore as elevated heart rate adversely affects the heart functioning and vital prognosis in patients 
with chronic heart failure, the specific heart rate lowering action of ivabradine helps to improve the heart 
functioning and vital prognosis in these patients. 
 
 
2. What you need to know before you take Ivabradine Zentiva 
 
Do not take Ivabradine Zentiva 

‒ If you are allergic to ivabradine or any of the other ingredients of this medicine (listed in section 6). 
‒ If your resting heart rate before treatment is too slow (below 70 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. 
‒ If you suffer from unstable angina (a severe form in which chest pain occurs very frequently and with 

or without exertion). 
‒ If you have heart failure which has recently become worse. 
‒ If your heartbeat is exclusively imposed by your 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) or diltiazem, verapamil (used for high blood pressure 
or angina pectoris). 

‒ If you are a woman able to have children and not using reliable contraception. 
‒ If you are pregnant or trying to become pregnant. 
‒ If you are breast-feeding. 

 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Ivabradine Zentiva 

‒ 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), or an abnormality 
of electrocardiogram (ECG) called “long QT syndrome”. 

‒ 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 suffer from symptoms of atrial fibrillation (pulse rate at rest unusually high (over 110 beats 
per minute) or irregular, without any apparent reason, making it difficult to measure). 

‒ If you have had a recent stroke (cerebral attack). 



35 

 

‒ If you suffer from mild to moderate low blood pressure. 
‒ If you suffer from uncontrolled blood pressure, especially after a change in your antihypertensive 

treatment. 
‒ If you suffer from severe heart failure or heart failure with abnormality of ECG called “bundle branch 

block”. 
‒ 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 Ivabradine 
Zentiva. 
 
Children 
Ivabradine Zentiva is not intended for use in children and adolescents younger than 18 years. 
 
Other medicines and Ivabradine Zentiva 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
Make sure to tell your doctor if you are taking any of the following medicines, as a dose adjustment 
of Ivabradine Zentiva or monitoring should be required: 

‒ Fluconazole (an antifungal medicine). 
‒ Rifampicin (an antibiotic). 
‒ Barbiturates (for difficult sleeping or epilepsy). 
‒ Phenytoin (for epilepsy). 
‒ St. John’s Wort (Hypericum perforatum) (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). 

‒ Some types of diuretics which may cause decrease in blood potassium level, such as furosemide, 
hydrochlorothiazide, indapamide (used to treat oedema, high blood pressure). 

 
Ivabradine Zentiva with food and drink 
Avoid grapefruit juice during treatment with Ivabradine Zentiva. 
 
Pregnancy and breast-feeding 
Do not take Ivabradine Zentiva if you are pregnant or are planning to have a baby (see “Do not take 
Ivabradine Zentiva”). 
If you are pregnant and have taken Ivabradine Zentiva, talk to your doctor. 
Do not take Ivabradine Zentiva if you are able to become pregnant unless you use reliable contraceptive 
measures (see “Do not take Ivabradine Zentiva”). 



36 

 

Do not take Ivabradine Zentiva if you are breast-feeding (see “Do not take Ivabradine Zentiva”). Talk 
to your doctor if you are breast-feeding or intending to breast-feed as breastfeeding should be discontinued 
if you take Ivabradine Zentiva. 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
Ivabradine Zentiva 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. 
 
 
3. How to take Ivabradine Zentiva 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
Ivabradine Zentiva should be taken during meals. 
 
If you are being treated for stable angina pectoris 
The starting dose should not exceed one tablet of Ivabradine Zentiva 5 mg twice daily. If you still have 
angina symptoms and if you have tolerated the 5 mg twice daily dose well, the dose may be increased. 
The maintenance dose should not exceed 7.5 mg twice daily. Your doctor will prescribe 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 Ivabradine 
Zentiva 5 mg (corresponding to 2.5 mg ivabradine) in the morning and one half 5 mg tablet in the evening. 
 
If you are being treated for chronic heart failure 
The usual recommended starting dose is one tablet of Ivabradine Zentiva 5 mg twice daily increasing 
if necessary to one tablet of Ivabradine Zentiva 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 Ivabradine 
Zentiva 5 mg (corresponding to 2.5 mg ivabradine) in the morning and one half 5 mg tablet in the evening. 
 
If you take more Ivabradine Zentiva than you should 
A large dose of Ivabradine Zentiva 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 Ivabradine Zentiva 
If you forget to take a dose of Ivabradine Zentiva, 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 Ivabradine Zentiva. 
 
If you stop taking Ivabradine Zentiva 
As the treatment for angina or chronic heart failure is usually life-long, you should discuss with your 
doctor before stopping this medicinal product. 
If you think that the effect of Ivabradine Zentiva is too strong or too weak, talk to your doctor 
or pharmacist. 



37 

 

 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
The most common adverse reactions with this medicine are dose dependent and related to its mode 
of action: 
 
Very common (may affect more than 1 in 10 people) 

‒ Luminous visual phenomena (brief moments of increased brightness, most often caused by sudden 
changes in light intensity). They can also be described as a halo, coloured flashes, image 
decomposition or multiple images. They generally occur within the first two months of treatment 
after which they may occur repeatedly and resolve during or after treatment. 

 
Common (may affect up to 1 in 10 people) 

‒ Modification in the heart functioning (the symptoms are a slowing down of the heart rate). They 
particularly occur within the first 2 to 3 months of treatment initiation. 

 
Other side effects have also been reported: 
 
Common (may affect up to 1 in 10 people) 

‒ Irregular rapid contraction of the heart, abnormal perception of heartbeat, uncontrolled blood 
pressure, headache, dizziness and blurred vision (cloudy vision). 

 
Uncommon (may affect up to 1 in 100 people) 

‒ Palpitations and cardiac extra beats, feeling sick (nausea), constipation, diarrhoea, abdominal pain, 
spinning sensation (vertigo), difficulty breathing (dyspnoea), muscle cramps, 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), skin rash, angioedema (such 
as swollen face, tongue or throat, difficulty in breathing or swallowing), low blood pressure, fainting, 
feeling of tiredness, feeling of weakness, abnormal ECG heart tracing, double vision, impaired 
vision. 

 
Rare (may affect up to 1 in 1,000 people) 

‒ Urticaria, itching, skin reddening, feeling unwell. 
 
Very rare (may affect up to 1 in 10,000 people) 

‒ Irregular heartbeats. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed 
in Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


38 

 

5. How to store Ivabradine Zentiva 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
Store below 25 °C. Store in the original package in order to protect from moisture. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Ivabradine Zentiva contains 

‒ The active substance is ivabradine (as hydrochloride). Each film-coated tablet contains 5 mg 
ivabradine (as hydrochloride) or 7.5 mg ivabradine (as hydrochloride). 

‒ The other ingredients are in the tablet core: Mannitol, crospovidone, magnesium stearate, 
and in the film-coating: hypromellose, titanium dioxide, macrogol 400, glycerol. 

 
What Ivabradine Zentiva looks like and contents of the pack 
Ivabradine Zentiva 5 mg film-coated tablets are oblong, one side and both edges scored white tablets with 
dimensions 4.8×8.8 mm. The tablet can be divided into equal doses. 
Ivabradine Zentiva 7.5 mg film-coated tablets are white to off white, round tablet with diameter 7.1 mm. 
Ivabradine Zentiva is packed in OPA/Alu/PVC-Alu blisters and in paper carton. 
 
Tablets are available in packs of 14, 28, 56, 84, 98, 100, 112 film-coated tablets. 
Not all pack sizes may be marketed. 
 
Marketing authorisation holder 
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
Manufacturer(s) 
Zentiva, k.s. 
U Kabelovny 130 
102 37 Prague 10 
Czech Republic 
 
or 
 



39 

 

S.C. Zentiva S.A 
50 Theodor Pallady Blvd, 
District 3, 
032266 Bucharest 
Romania 
 
This leaflet was last revised in <{MM/YYYY}> 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET