IVABRADINE ZENTIVA 5mg tablets medication leaflet

Ivabradine Zentiva 5 mg film-coated tablets

Ivabradine Zentiva 7.5 mg film-coated tablets

Ivabradine Zentiva 5 mg film-coated tablets

Each film-coated tablet contains 5 mg ivabradine (as hydrochloride).

Ivabradine Zentiva 7.5 mg film-coated tablets

Each film-coated tablet contains 7.5 mg ivabradine (as hydrochloride).

For the full list of excipients, see section 6.1.

Film-coated tablet

Ivabradine Zentiva 5 mg film-coated tablets

Round, biconvex white tablets with deep breakline on one side and ‘5’ debossing on other side withdiameter 6.5 mm. The tablet can be divided into equal doses.

Ivabradine Zentiva 7.5 mg film-coated tablets

White to off white, round tablets with diameter 7.1 mm.

Symptomatic treatment of chronic stable angina pectoris

Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary arterydisease adults with normal sinus rhythm and heart rate ≥ 70 beats per minute (bpm). Ivabradineis indicated:‒ in adults unable to tolerate or with a contraindication to the use of beta-blockersor‒ in combination with beta-blockers in patients inadequately controlled with an optimal beta-blockerdose.

Treatment of chronic heart failure

Ivabradine is indicated in chronic heart failure NYHA II to IV class with systolic dysfunction, in adultpatients in sinus rhythm and whose heart rate is ≥ 75 bpm, in combination with standard therapy includingbeta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated (see section 5.1).

Symptomatic treatment of chronic stable angina pectoris

It is recommended that the decision to initiate or titrate treatment takes place with the availability of serialheart 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 toleratedand if resting heart rate remains above 60 bpm, the dose may be increased to the next higher dosein patients receiving 2.5 mg twice daily or 5 mg twice daily. The maintenance dose should not exceed7.5 mg twice daily.

If there is no improvement in symptoms of angina within 3 months after start of treatment, treatmentof ivabradine should be discontinued.

In addition, discontinuation of treatment should be considered if there is only limited symptomaticresponse and when there is no clinically relevant reduction in resting heart rate within three months.

If, during treatment, heart rate decreases below 50 bpm at rest or the patient experiences symptoms relatedto bradycardia such as dizziness, fatigue or hypotension, the dose must be titrated downward includingthe lowest dose of 2.5 mg twice daily (one half 5 mg tablet twice daily). After dose reduction, heart rateshould be monitored (see section 4.4). Treatment must be discontinued if heart rate remains below 50 bpmor 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 heartfailure.

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 bpmor decreased to 2.5 mg twice daily (one half 5 mg tablet twice daily) if resting heart rate is persistentlybelow 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 bpm at rest or the patient experiencessymptoms related to bradycardia, the dose must be titrated downward to the next lower dose in patientsreceiving 7.5 mg twice daily or 5 mg twice daily. If heart rate increases persistently above 60 bpm at rest,the dose can be up titrated to the next upper dose in patients receiving 2.5 mg twice daily or 5 mg twicedaily.

Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist(see section 4.4).

In patients aged 75 years or more, a lower starting dose should be considered (2.5 mg twice daily i.e. onehalf 5 mg tablet twice daily) before up-titration if necessary.

No dose adjustment is required in patients with renal insufficiency and creatinine clearanceabove 15 mL/min (see section 5.2).

No data are available in patients with creatinine clearance below 15 mL/min. Ivabradine should thereforebe used with precaution in this population.

No dose adjustment is required in patients with mild hepatic impairment. Caution should be exercisedwhen using ivabradine in patients with moderate hepatic impairment. Ivabradine is contraindicated for usein patients with severe hepatic insufficiency, since it has not been studied in this population and a largeincrease in systemic exposure is anticipated (see sections 4.3 and 5.2).

The safety and efficacy of ivabradine in children aged below 18 years have not been established.

Currently available data for the treatment of chronic heart failure are described in sections 5.1 and 5.2but no recommendation on a posology can be made.

No data for symptomatic treatment of chronic stable angina pectoris are available.

Tablets must be taken orally twice daily, i.e. once in the morning and once in the evening during meals(see section 5.2). Ivabradine Zentiva 5 mg film-coated tablet can be divided into equal doses. Use a tabletcutter to divide the tablet.

‒ 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 and5.2).

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

‒ Pregnancy, lactation and women of childbearing potential not using appropriate contraceptivemeasures (see section 4.6).

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 becauseivabradine 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, ECGor ambulatory 24-hour monitoring should be considered when determining resting heart rate beforeinitiation 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).

Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses itsefficacy when a tachyarrhythmia occurs (e.g. ventricular or supraventricular tachycardia). Ivabradineis therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interferewith 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 Ianti-arrhythmics. It is recommended to regularly clinically monitor ivabradine treated patientsfor the occurrence of atrial fibrillation (sustained or paroxysmal), which should also include ECGmonitoring 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 theirphysician if these occur.

If atrial fibrillation develops during treatment, the balance of benefits and risks of continued ivabradinetreatment should be carefully reconsidered.

Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundlebranch 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 bpm(see section 4.3).

If, during treatment, resting heart rate decreases persistently below 50 bpm or the patient experiencessymptoms related to bradycardia such as dizziness, fatigue or hypotension, the dose must be titrateddownward 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 verapamilor diltiazem is contraindicated (see sections 4.3 and 4.5). No safety issue has been raisedon the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers suchas amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine calcium channelblockers has not been established (see section 5.1).

Chronic heart failure

Heart failure must be stable before considering ivabradine treatment. Ivabradine should be used withcaution in heart failure patients with NYHA functional classification IV due to limited amount of datain this population.

Stroke

The use of ivabradine is not recommended immediately after a stroke since no data is available in thesesituations.

Visual function

Ivabradine influences retinal function. There is no evidence of a toxic effect of long-term ivabradinetreatment on the retina (see section 5.1). Cessation of treatment should be considered if any unexpecteddeterioration in visual function occurs. Caution should be exercised in patients with retinitis pigmentosa.

Patients with hypotension

Limited data are available in patients with mild to moderate hypotension, and ivabradine should thereforebe used with caution in these patients. Ivabradine is contraindicated 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 pharmacologicalcardioversion 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 medicinalproducts should be avoided (see section 4.5). If the combination appears necessary, close cardiacmonitoring is needed.

Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give riseto severe arrhythmias, in particular Torsade de pointes.

Hypertensive patients requiring blood pressure treatment modifications

When treatment modifications are made in chronic heart failure patients treated with ivabradine bloodpressure should be monitored at an appropriate interval (see section 4.8).

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 withivabradine 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 resultingcombination 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.

Ivabradine is metabolised by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradinewas 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 andinfluence its metabolism and pharmacokinetics to a clinically significant extent. Interaction studies haveestablished that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decreasethem. Increased plasma concentrations of ivabradine may be associated with the risk of excessivebradycardia (see section 4.4).

Contraindication of concomitant use

Potent CYP3A4 inhibitors

The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole),macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV proteaseinhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated (see section 4.3). The potent CYP3A4inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased ivabradine meanplasma exposure by 7 to 8-fold.

Moderate CYP3A4 inhibitors

Specific interaction studies in healthy volunteers and patients have shown that the combination ofivabradine with the heart rate reducing agents diltiazem or verapamil resulted in an increase in ivabradineexposure (2 to 3-fold increase in AUC) and an additional heart rate reduction of 5 bpm. The concomitantuse of ivabradine with these medicinal products is contraindicated (see section 4.3).

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 beconsidered at the starting dose of 2.5 mg twice daily and if resting heart rate is above 70 bpm, withmonitoring of heart rate.

CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum perforatum [St. John’s Wort]) maydecrease ivabradine exposure and activity. The concomitant use of CYP3A4 inducing medicinal productsmay require an adjustment of the dose of ivabradine. The combination of ivabradine 10 mg twice dailywith St. John’s Wort was shown to reduce ivabradine AUC by half. The intake of St. John’s Wort shouldbe restricted during the treatment with ivabradine.

Other concomitant use

Specific interaction studies have shown no clinically significant effect of the following medicinal productson pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors (omeprazole,lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), dihydropyridine calcium channelblockers (amlodipine, lacidipine), digoxin and warfarin. In addition there was no clinically significanteffect of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on thepharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.

In pivotal phase III clinical trials the following medicinal products were routinely combinedwith 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.

Interaction studies have only been performed in adults.

Women of childbearing potential should use appropriate contraceptive measures during treatment(see section 4.3).

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 embryotoxicand teratogenic effects (see section 5.3). The potential risk for humans is unknown. Therefore, ivabradineis contraindicated during pregnancy (see section 4.3).

Animal studies indicate that ivabradine is excreted in milk. Therefore, ivabradine is contraindicated duringbreast-feeding (see section 4.3). Women that need treatment with ivabradine should stop breast-feeding,and choose for another way of feeding their child.

Studies in rats have shown no effect on fertility in males and females (see section 5.3).

Ivabradine has no or negligible influence on the ability to use machines.

A specific study to assess the possible influence of ivabradine on driving performance has been performedin 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 usingmachines in situations where sudden variations in light intensity may occur, especially when drivingat night.

The most common adverse reactions with ivabradine are luminous phenomena (phosphenes) (14.5%)and bradycardia (3.3 %). They are dose dependent and related to the pharmacological effect of themedicinal product.

The following adverse reactions have been reported during clinical trials and are ranked usingthe following frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimatedfrom 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 monthof treatment

Dizziness, possibly related to bradycardia

Uncommon* Syncope, possibly related to bradycardia

System organ class Frequency Preferred term

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 PQinterval)

Ventricular extrasystoles

Atrial fibrillation

Uncommon Palpitations

Supraventricular extrasystoles

ECG prolonged QT interval

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 Uncommon Dyspnoeadisorders

Gastrointestinal disorders Uncommon Nausea

Abdominal pain*

Skin and subcutaneous tissue Uncommon* Angioedemadisorders Rash

Rare* Erythema

Pruritus

Urticaria

Musculoskeletal and connective tissue Uncommon Muscle spasmsdisorders

Renal and urinary disorders Uncommon Elevated creatinine in blood

General disorders and administration Uncommon* Asthenia, possibly related to bradycardiasite conditions Fatigue, possibly related to bradycardia

Rare* Malaise, possibly related to bradycardia

* Frequency calculated from clinical trials for adverse events detected from spontaneous report.

Luminous phenomena (phosphenes)

Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhancedbrightness in a limited area of the visual field. They are usually triggered by sudden variations in lightintensity. Phosphenes may also be described as a halo, image decomposition (stroboscopicor kaleidoscopic effects), coloured bright lights, or multiple image (retinal persistency). The onsetof 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 duringor after treatment, of which a majority (77.5%) resolved during treatment. Fewer than 1% of patientschanged their daily routine or discontinued the treatment in relation with phosphenes.

Bradycardia

Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatmentinitiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.

Atrial fibrillation

In the SIGNIFY study atrial fibrillation was observed in 5.3% of patients taking ivabradine comparedto 3.8% in the placebo group. In a pooled analysis of all the Phase II/III double blind controlled clinicaltrials with a duration of at least 3 months including more than 40 000 patients, the incidence of atrialfibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, correspondingto a hazard ratio of 1.26, 95% CI [1.15 - 1.39].

In the SHIFT trial more patients experienced episodes of increased blood pressure while treated withivabradine (7.1%) compared to patients treated with placebo (6.1%). These episodes occurred mostfrequently shortly after blood pressure treatment was modified, were transient, and did not affectthe treatment effect of ivabradine.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Overdose may lead to severe and prolonged bradycardia (see section 4.8).

Severe bradycardia should be treated symptomatically in a specialised environment. In the eventof bradycardia with poor haemodynamic tolerance, symptomatic treatment including intravenous beta-stimulating medicinal products such as isoprenaline may be considered. Temporary cardiac electricalpacing may be instituted if required.

Pharmacotherapeutic group: Cardiac therapy, other cardiac preparations, ATC code: C01EB17

Ivabradine is a pure heart rate lowering agent, acting by selective and specific inhibition of the cardiacpacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulatesheart rate. The cardiac effects are specific to the sinus node with no effect on intra-atrial, atrioventricularor 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 participatesin 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 ivabradineunderlies the luminous phenomena that may be occasionally experienced by patients. Luminousphenomena (phosphenes) are described as a transient enhanced brightness in a limited area of the visualfield (see section 4.8).

The main pharmacodynamic property of ivabradine in humans is a specific dose dependent reductionin heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily indicates a trend towardsa plateau effect which is consistent with a reduced risk of severe bradycardia below 40 bpm (see section4.8).

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 notinfluence intracardiac conduction, contractility (no negative inotropic effect) or ventricular repolarisation:‒ in clinical electrophysiology studies, ivabradine had no effect on atrioventricular or intraventricularconduction times or corrected QT intervals.‒ in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) between30 and 45%), ivabradine did not have any deleterious influence on LVEF.

The antianginal and anti-ischaemic efficacy of ivabradine was studied in five double-blind randomisedtrials (three versus placebo, and one each versus atenolol and amlodipine). These trials included a totalof 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 weeksof treatment. Efficacy was confirmed with 7.5 mg twice daily. In particular, the additional benefit over5 mg twice daily was established in a reference-controlled study versus atenolol: total exercise durationat trough was increased by about 1 minute after one month of treatment with 5 mg twice daily and furtherimproved by almost 25 seconds after an additional 3-month period with forced titration to 7.5 mg twicedaily. In this study, the antianginal and anti-ischaemic benefits of ivabradine were confirmed in patientsaged 65 years or more. The efficacy of 5 and 7.5 mg twice daily was consistent across studies on exercisetest parameters (total exercise duration, time to limiting angina, time to angina onset and time to 1 mm STsegment 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 activity (12 hours after oral intake).

In a 725-patients randomised placebo-controlled study, ivabradine did not show additional efficacy on topof amlodipine 10 mg o.d. at the trough of activity (12 hours after oral intake) while an additional efficacywas shown at peak (3 - 4 hours after oral intake).

In a 1 277-patients randomised placebo-controlled study, ivabradine demonstrated a statisticallysignificant additional efficacy on response to treatment (defined as a decrease of at least 3 anginaattacks per week and/or an increase in the time to 1 mm ST segment depression of at least 60 s duringa treadmill ETT) on top of amlodipine 5 mg o.d. or nifedipine GITS 30 mg o.d. at the trough of 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 ETTparameters at the trough of activity while an additional efficacy was shown at peak (3 - 4 hours afteroral ivabradine intake).

Ivabradine efficacy was fully maintained throughout the 3- or 4-month treatment periods in the efficacytrials. There was no evidence of pharmacological tolerance (loss of efficacy) developing during treatmentnor of rebound phenomena after abrupt treatment discontinuation. The antianginal and anti-ischaemiceffects of ivabradine were associated with dose-dependent reductions in heart rate and with a significantdecrease in rate pressure product (heart rate x 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 oneyear (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 andleft ventricular dysfunction (LVEF < 40%) on top of optimal background therapy with 86.9% of patientsreceiving beta-blockers. The main efficacy criterion was the composite of cardiovascular death,hospitalisation for acute MI or hospitalisation for new onset or worsening heart failure. The study showedno difference in the rate of the primary composite outcome in the ivabradine group by comparisonto 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 signalwas identified regarding cardiovascular death, hospitalisation for acute MI or heart failure (ivabradine12.0% versus placebo 15.5%, p = 0.05).

A large outcome study, SIGNIFY, was performed in 19 102 patients with coronary artery disease andwithout clinical heart failure (LVEF > 40%), on top of optimal background therapy. A therapeutic schemehigher than the approved posology was used (starting dose 7.5 mg twice daily (5 mg twice daily, if age≥ 75 years) and titration up to 10 mg twice daily.). The main efficacy criterion was the compositeof cardiovascular death or non-fatal MI. The study showed no difference in the rate of the primarycomposite endpoint (PCE) in the ivabradine group by comparison to the placebo group (relative riskivabradine/placebo 1.08, p = 0.197). Bradycardia was reported by 17.9 % of patients in the ivabradinegroup (2.1% in the placebo group). Verapamil, diltiazem or strong CYP 3A4 inhibitors were receivedby 7.1% of patients during the study.

A small statistically significant increase in the PCE was observed in a pre-specified subgroup of patientswith 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 populationin 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 controlledoutcome trial conducted in 6 505 adult patients with stable chronic CHF (for ≥ 4 weeks), NYHA class IIto 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 IIantagonists (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 bpmfrom a baseline value of 80 bpm. The difference in heart rate between ivabradine and placebo arms was10.8 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 rateof the primary composite endpoint of cardiovascular mortality and hospitalisation for worsening heartfailure (hazard ratio: 0.82, 95% CI [0.75; 0.90], p < 0.0001) apparent within 3 months of initiation oftreatment. The absolute risk reduction was 4.2%. The results on the primary endpoint are mainly driven bythe 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 Placebo Hazard ratio p-value(N = 3 241) (N = 3 264) [95% CI]n (%) n (%)

Primary composite endpoint 793 (24.47) 937 (28.71) 0.82 [0.75; 0.90] < 0.0001

Components of the composite:‒ CV death 449 (13.85) 491 (15.04) 0.91 [0.80; 1.03] 0.128‒ Hospitalisation for worsening HF 514 (15.86) 672 (20.59) 0.74 [0.66; 0.83] < 0.0001

Other secondary endpoints‒ All cause death 503 (15.52) 552 (16.91) 0.90 [0.80; 1.02] 0.092‒ Death from HF 113 (3.49) 151 (4.63) 0.74 [0.58;0.94] 0.014‒ Hospitalisation for any cause 1 231 (37.98) 1 356 (41.54) 0.89 [0.82;0.96] 0.003‒ Hospitalisation for CV reason 977 (30.15) 1 122 (34.38) 0.85 [0.78; 0.92] 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.

In the subgroup of patients with heart rate ≥ 75 bpm (n = 4 150), a greater reduction was observedin 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 subgroupof 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 patientsreceiving beta-blocker therapy (hazard ratio: 0.85, 95% CI [0.76; 0.94]). In the subgroup of patients withheart rate ≥ 75 bpm and on the recommended target dose of beta-blocker, no statistically significantbenefit was observed on the primary composite endpoint (hazard ratio: 0.97, 95% CI [0.74; 1.28]) andother 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 patientson 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 ophthalmologicinvestigations, aiming at documenting the function of the cone and rod systems and the ascending visualpathway (i.e. electroretinogram, static and kinetic visual fields, colour vision, visual acuity), in patientstreated with ivabradine for chronic stable angina pectoris over 3 years, did not show any retinal toxicity.

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 dilatedcardiomyopathy (DCM) on top of optimal background treatment. 74 received ivabradine (ratio 2:1).

The starting dose was 0.02 mg/kg twice daily in age-subset [6 - 12] months, 0.05 mg/kg twice dailyin [1 - 3] years and [3 - 18] years < 40 kg, and 2.5 mg twice daily in [3 - 18] years and ≥ 40 kg.

The dose was adapted depending on the therapeutic response with maximum doses of 0.2 mg/kg twicedaily, 0.3 mg/kg twice daily and 15 mg twice daily, respectively. In this study, ivabradine wasadministered as oral liquid formulation or tablet twice daily. The absence of pharmacokineticdifference between the 2 formulations was shown in an open-label randomised two-period cross-overstudy in 24 adult healthy volunteers.

A 20% heart rate reduction, without bradycardia, was achieved by 69.9% of patients in the ivabradinegroup 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 twice daily,0.10±0.04 mg/kg twice daily and 4.1±2.2 mg twice daily in the age subsets [1 - 3] years, [3 - 18] yearsand < 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 patientsversus 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 mortalityhave not been studied.

The European Medicines Agency has waived the obligation to submit the results of studies with thereference medicinal product containing ivabradine in all subsets of the paediatric population for thetreatment of angina pectoris (see section 4.2 for information on paediatric use).

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

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 levelreached in about 1 hour under fasting condition. The absolute bioavailability of the film-coated tabletsis 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 variabilityin exposure (see section 4.2).

Ivabradine is approximately 70% plasma protein bound and the volume of distribution at steady-stateis close to 100 L in patients. The maximum plasma concentration following chronic administrationat the recommended dose of 5 mg twice daily is 22 ng/mL (CV = 29%). The average plasma concentrationis 10 ng/mL (CV = 38%) at steady-state.

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) withan exposure about 40% of that of the parent compound. The metabolism of this active metabolite alsoinvolves CYP3A4. Ivabradine has low affinity for CYP3A4, shows no clinically relevant CYP3A4induction or inhibition and is therefore unlikely to modify CYP3A4 substrate metabolism or plasmaconcentrations. Inversely, potent inhibitors and inducers may substantially affect ivabradine plasmaconcentrations (see section 4.5).

Ivabradine is eliminated with a main half-life of 2 hours (70 - 75% of the AUC) in plasmaand an effective half-life of 11 hours. The total clearance is about 400 mL/min and the renal clearanceis 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.

No pharmacokinetic differences (AUC and Cmax) have been observed between elderly (≥ 65 years) or veryelderly patients (≥ 75 years) and the overall population (see section 4.2).

The impact of renal impairment (creatinine clearance from 15 to 60 mL/min) on ivabradinepharmacokinetic is minimal, in relation with the low contribution of renal clearance (about 20%) to totalelimination for both ivabradine and its main metabolite S 18982 (see section 4.2).

In patients with mild hepatic impairment (Child Pugh score up to 7) unbound AUC of ivabradine andthe main active metabolite were about 20% higher than in subjects with normal hepatic function. Data areinsufficient to draw conclusions in patients with moderate hepatic impairment. No data are availablein patients with severe hepatic impairment (see sections 4.2 and 4.3).

The pharmacokinetic profile of ivabradine in paediatric chronic heart failure patients aged 6 monthsto less than 18 years is similar to the pharmacokinetics described in adults when a titration scheme basedon age and weight is applied.

Pharmacokinetic/pharmacodynamic (PK/PD) relationship

PK/PD relationship analysis has shown that heart rate decreases almost linearly with increasing ivabradineand 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 reacha plateau. High exposures to ivabradine that may occur when ivabradine is given in combination withstrong CYP3A4 inhibitors may result in an excessive decrease in heart rate although this risk is reducedwith moderate CYP3A4 inhibitors (see sections pct. 4.3, pct. 4.4 and 4.5).

The PK/PD relationship of ivabradine in paediatric chronic heart failure patients aged 6 months to lessthan 18 years is similar to the PK/PD relationship described in adults.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductive toxicity studiesshowed no effect of ivabradine on fertility in male and female rats. When pregnant animals were treatedduring organogenesis at exposures close to therapeutic doses, there was a higher incidence of foetuseswith 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 retinalfunction were observed but were not associated with any damage to ocular structures. These data areconsistent 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.

The environmental risk assessment of ivabradine has been conducted in accordance to Europeanguidelines on ERA.

Outcomes of these evaluations support the lack of environmental risk of ivabradine and ivabradine doesnot pose a threat to the environment.

Mannitol

Crospovidone (type A)

Magnesium stearate

Hypromellose (6 mPa·s, type 2910)

Titanium dioxide (E172)

Macrogol 400

Glycerol (E422)

Not applicable.

2 years.

Store below 25 °C.

Store in the original package in order to protect from moisture.

OPA/Alu/PVC-Alu blisters

Ivabradine Zentiva 5 mg film-coated tablets

Pack sizes: 14, 28, 56, 84, 98, 100, 112 film-coated tablets

Ivabradine Zentiva 7.5 mg film-coated tablets

Pack sizes: 14, 28, 56, 84, 98, 100, 112 film-coated tablets

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Zentiva, k.s.

U Kabelovny 130102 37 Prague 10

Czech Republic

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

Date of first authorisation: 11 November 2016

Date of latest renewal: 29 September 2021

Detailed information on this medicinal product is available on the website of the European Medicines

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