Bravadin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Bravadin® (Bravadin®)

Composition:

Active substance: ivabradine;

One film-coated tablet contains 5 mg of ivabradine, equivalent to 5.39 mg of ivabradine hydrochloride, or 7.5 mg of ivabradine, equivalent to 8.085 mg of ivabradine hydrochloride;

Excipients: lactose monohydrate, magnesium stearate, maize starch, maltodextrin, colloidal anhydrous silicon dioxide, hypromellose;

Film coating: hypromellose, titanium dioxide (E 171), talc, propylene glycol, iron oxide yellow (E 172), iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg: pale reddish-orange, rectangular, slightly biconvex, film-coated tablets with a score line on one side;

7.5 mg: pale reddish-orange, round, slightly biconvex, film-coated tablets with beveled edges.

Pharmacotherapeutic group. Cardiac drugs. Other cardiac drugs.
ATC Code C01E B17.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Ivabradine is a substance that reduces heart rate (HR) by acting on the cardiac pacemaker through selective and specific inhibition of the I_f current, which controls spontaneous diastolic depolarization in the sinus node and regulates HR. Ivabradine acts exclusively on the sinus node and does not affect intra-atrial, atrioventricular, or intraventricular conduction, myocardial contractility, or ventricular repolarization.

Ivabradine may also interact with the Ih current in the retinal cells, which is structurally similar to the I_f current in the cardiac sinus node. This interaction underlies the development of transient visual disturbances due to reduced retinal response to bright light stimuli. Under triggering conditions (sudden changes in lighting), partial inhibition of the Ih current by ivabradine may lead to unexpected visual phenomena in patients. These visual phenomena (phosphenes) manifest as a temporary increase in brightness in a limited area of the visual field (see section "Adverse Reactions").

Pharmacodynamic Effects

The main pharmacodynamic property of ivabradine is selective, dose-dependent reduction of HR. Analysis of HR reduction with ivabradine doses < 20 mg twice daily showed a tendency toward a plateau effect, reducing the risk of severe bradycardia < 40 beats per minute (bpm) (see section "Adverse Reactions").

When administered at recommended therapeutic doses (5–7.5 mg twice daily), ivabradine reduces HR by approximately 10 bpm at rest and during exercise. This reduces cardiac workload and myocardial oxygen consumption. Ivabradine does not affect intracardiac conduction, myocardial contractility (no negative inotropic effect), or ventricular repolarization:

• In clinical electrophysiological studies, ivabradine did not affect atrioventricular or intraventricular conduction or corrected QT interval;
• In patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] of 30–45%), ivabradine showed no negative effect on LVEF parameters.

Clinical Efficacy and Safety

Anti-anginal and anti-ischemic efficacy of ivabradine has been demonstrated in clinical trials.

These properties of ivabradine have been confirmed in patients over 65 years of age. The efficacy of ivabradine at doses of 5 and 7.5 mg twice daily was consistent across all studies, as measured by exercise testing parameters (total exercise duration, time to onset of angina-limiting symptoms, time to onset of angina, time to 1 mm ST-segment depression), and was associated with approximately a 70% reduction in the number of angina attacks. The twice-daily dosing regimen of ivabradine provided stable and effective action over 24 hours.

In a study where ivabradine was administered in addition to atenolol 50 mg daily, additional efficacy was observed in all exercise test parameters 12 hours after dosing.

Efficacy studies demonstrated that the effectiveness of ivabradine is fully maintained over 3 to 4 months of treatment. During these studies, no cases of pharmacological tolerance (loss of efficacy) or rebound effect after abrupt discontinuation were observed. The anti-anginal and anti-ischemic efficacy of ivabradine was associated with dose-dependent reduction in HR and significant reduction in the rate-pressure product (RPP), reflecting myocardial oxygen demand at rest and during physical exertion (RPP = HR × systolic blood pressure). The effect of ivabradine on blood pressure (BP) and peripheral vascular resistance was minimal and not clinically significant.

Long-term studies have confirmed the sustained effect of ivabradine on HR reduction and demonstrated no effect of ivabradine on glucose and lipid metabolism.

Anti-ischemic and anti-anginal efficacy and safety of ivabradine have been confirmed in patients with diabetes mellitus.

In a large morbidity and mortality study in patients with ischemic heart disease and left ventricular dysfunction (LVEF < 40%), ivabradine was administered on top of optimal background therapy (86.9% of patients received beta-blockers). The primary efficacy endpoint was the total number of cardiovascular deaths, hospitalizations due to myocardial infarction, and hospitalizations due to onset or worsening of heart failure (HF). The study showed no significant difference in reduction of the primary composite endpoint between the ivabradine and placebo groups.

In another large morbidity and mortality study in patients with ischemic heart disease without clinical signs of heart failure (LVEF > 40%), ivabradine was administered on top of optimal background therapy. In this study, a higher-dose regimen than approved was used (initial dose: 7.5 mg twice daily [5 mg twice daily for patients aged 75 years or older], with dose titration up to 10 mg twice daily). The primary efficacy endpoint was a composite of cardiovascular death or non-fatal myocardial infarction. The study did not show a difference in the incidence of the primary composite endpoint between the ivabradine and placebo groups. Bradycardia occurred in 17.9% of patients in the ivabradine group (2.1% in the placebo group). During the study, 7.1% of patients received verapamil, diltiazem, or strong CYP3A4 inhibitors.

A small but statistically significant increase in the incidence of the primary composite endpoint was observed in a predefined subgroup of patients with class II or higher angina according to the Canadian Cardiovascular Society (CCS) classification (3.4% per year vs. 2.9%); however, no such effect was observed in the overall population of patients with CCS class ≥ I angina. The use of a higher-than-approved dose in the study partially explains these results.

A morbidity and mortality study included patients with chronic systolic heart failure (CHF) of NYHA functional class II–IV [New York Heart Association classification], duration ≥ 4 weeks, left ventricular dysfunction (LVEF ≤ 35%), and resting HR ≥ 70 bpm.

Patients received standard therapy, including beta-blockers (89%), angiotensin-converting enzyme inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and aldosterone antagonists (60%). In the ivabradine group, 67% of patients received the drug at a dose of 7.5 mg twice daily. Ivabradine treatment was associated with a mean reduction in HR of 15 bpm compared to a baseline of 80 bpm.

This study demonstrated a clinically and statistically significant reduction in the risk of cardiovascular mortality and hospitalization for worsening heart failure within the first 3 months of therapy.

The reduction in risk was observed independently of gender, NYHA class, ischemic or non-ischemic etiology of heart failure, and presence of comorbidities (diabetes or arterial hypertension).

The study demonstrated a significant reduction in the risk of cardiovascular events in the overall group of patients receiving beta-blocker therapy. In the subgroup of patients with HR ≥ 75 bpm receiving recommended doses of beta-blockers, no statistically significant effect was observed on the primary composite endpoint or other secondary endpoints, including hospitalization for worsening HF or HF-related death.

In 28% of patients in the ivabradine group, there was a significant improvement in functional class (NYHA classification) compared to 24% in the placebo group.

Controlled ophthalmological assessments of the photoreceptor system and visual pathways (electroretinograms, static and dynamic visual fields, color vision, and visual acuity) in 97 patients treated with ivabradine for chronic stable angina over 3 years showed no evidence of retinal toxicity.

Pharmacokinetics

Under physiological conditions, ivabradine is rapidly released and highly water-soluble (> 10 mg/mL). Ivabradine is the S-enantiomer and has not shown in vivo biotransformation. The main active metabolite of ivabradine is the N-desmethyl derivative.

Absorption and Bioavailability

After oral administration, ivabradine is rapidly and almost completely absorbed. When administered fasting, maximum plasma concentration (C_max) is reached within approximately 1 hour. The absolute bioavailability of ivabradine is about 40%, due to first-pass metabolism in the gut and liver. Taking the drug with food delays absorption by approximately 1 hour and increases plasma concentration by 20–30%. To avoid fluctuations in plasma concentration, the drug is recommended to be taken with meals (see section "Dosage and Administration").

Distribution

Approximately 70% of ivabradine is bound to plasma proteins. The volume of distribution at steady state is about 100 L. With long-term administration of the recommended initial dose of 5 mg twice daily, C_max in plasma is approximately 22 ng/mL (CV = 29%). The mean plasma concentration at steady state is 10 ng/mL (CV = 38%).

Biotransformation

Ivabradine is extensively metabolized in the liver and intestine via the cytochrome P450 3A4 (CYP3A4) system. The main active metabolite of ivabradine is its N-desmethyl derivative (S18982), with a plasma concentration of about 40% of that of ivabradine hydrochloride. The main active metabolite is also metabolized by the CYP3A4 system. Ivabradine has low affinity for CYP3A4, does not induce or inhibit it, and therefore is unlikely to alter the metabolism or plasma concentration of CYP3A4 substrates. However, CYP3A4 inhibitors and inducers can significantly affect the plasma concentration of ivabradine (see section "Interaction with Other Medicinal Products and Other Forms of Interactions").

Elimination

The main elimination half-life of ivabradine is 2 hours (70–75% of the area under the plasma concentration-time curve [AUC]), and the effective half-life is 11 hours. Total clearance of ivabradine is 400 mL/min, and renal clearance is 70 mL/min. Metabolites are excreted equally in urine and feces. Approximately 4% of the active substance is excreted unchanged in urine.

Linearity/Non-linearity

The pharmacokinetics of ivabradine in doses of 0.5–24 mg is linear.

Special Patient Groups

• Elderly patients (65–75 years): Pharmacokinetic parameters (AUC and C_max) in this age group do not differ from those in the general patient population (see section "Dosage and Administration").
• Renal impairment: The effect of renal impairment (creatinine clearance 15–60 mL/min) on ivabradine pharmacokinetics is minimal due to the small contribution of renal clearance (about 20%) to the total clearance of ivabradine and its main metabolite S18982 (see section "Dosage and Administration").
• Hepatic impairment: In patients with mild hepatic impairment (Child-Pugh score ≤ 7), unbound AUC of ivabradine and its main active metabolite was 20% higher than in patients with normal liver function. Data on ivabradine pharmacokinetics in patients with moderate hepatic impairment are limited; data in patients with severe hepatic impairment are lacking (see sections "Contraindications" and "Dosage and Administration").

Pharmacokinetic/Pharmacodynamic Relationship

Analysis of the pharmacokinetic/pharmacodynamic relationship demonstrated a linear relationship between HR reduction and increasing plasma concentrations of ivabradine and its active metabolite at doses of 15–20 mg twice daily. At higher doses, HR reduction becomes disproportionate to plasma concentration and tends to plateau. High plasma concentrations of ivabradine may result from co-administration with strong CYP3A4 inhibitors, potentially leading to significant HR reduction; however, the risk is reduced when ivabradine is used with moderate CYP3A4 inhibitors (see sections "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interactions", and "Special Warnings and Precautions for Use").

Clinical characteristics.

Indications.

Symptomatic treatment of chronic stable angina.

Ivabradine is indicated for symptomatic treatment of chronic stable angina in adult patients with ischemic heart disease, normal sinus rhythm, and heart rate ≥ 70 beats per minute (bpm).

The drug should be prescribed:

• to patients who have contraindications or limitations to the use of beta-blockers;
• in combination with beta-blockers to patients whose condition is not adequately controlled with optimal doses of beta-blockers.

Treatment of chronic heart failure.

Ivabradine is indicated in chronic heart failure class II–IV (according to NYHA classification) with systolic dysfunction in adult patients with sinus rhythm and heart rate ≥ 75 bpm, in combination with standard therapy including beta-blockers, or when beta-blockers are contraindicated or poorly tolerated (see section «Pharmacodynamics»).

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Resting heart rate < 70 bpm before initiation of treatment.
• Cardiogenic shock.
• Acute myocardial infarction.
• Severe arterial hypotension (blood pressure < 90/50 mm Hg).
• Severe hepatic impairment.
• Sinus node dysfunction syndrome.
• Sinoatrial block.
• Unstable or acute heart failure.
• Presence of a cardiac pacemaker in the patient (heart rate is controlled exclusively by the pacemaker).
• Unstable angina.
• Third-degree AV block.
• Combination with strong CYP3A4 inhibitors: antifungal agents – azole derivatives (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir), and nefazodone (see sections «Pharmacokinetics» and «Interaction with other medicinal products and other forms of interaction»).
• Concomitant use with verapamil or diltiazem, which are moderate CYP3A4 inhibitors with heart rate-lowering properties (see section «Interaction with other medicinal products and other forms of interaction»).
• Pregnancy, breastfeeding. Also contraindicated in women of childbearing potential who are not using appropriate contraceptive measures (see section «Use during pregnancy or breastfeeding»).

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Not recommended combinations

Drugs that prolong the QT interval

• Cardiovascular: quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone.
• Non-cardiovascular: pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin.

Concomitant use of ivabradine with cardiovascular and non-cardiovascular drugs that prolong the QT interval should be avoided, as reduction in heart rate may exacerbate QT interval prolongation. If such combination is necessary, careful cardiac monitoring should be ensured (see section «Special precautions for use»).

Combinations requiring caution in use

Diuretics (thiazide and loop diuretics)

Hypokalemia increases the risk of arrhythmias. Ivabradine may cause bradycardia, which, in the presence of hypokalemia, may trigger severe arrhythmias, particularly in patients with congenital or drug-induced long QT syndrome.

Pharmacokinetic interactions

Ivabradine is metabolized exclusively by cytochrome CYP3A4 and is a very weak inhibitor of this enzyme. It has been confirmed that ivabradine does not affect the metabolism and plasma concentrations of other CYP3A4 substrates (weak, moderate, and strong). Inhibitors and inducers of CYP3A4 may interact with ivabradine, resulting in clinically significant effects on its metabolism and pharmacokinetics. Studies investigating drug interactions have confirmed that CYP3A4 inhibitors increase plasma concentrations of ivabradine, while CYP3A4 inducers decrease them. Increased plasma concentrations of ivabradine increase the risk of excessive bradycardia (see section «Special precautions for use»).

Contraindicated combinations

Strong CYP3A4 inhibitors

Concomitant use of ivabradine with strong CYP3A4 inhibitors such as antifungal azole derivatives (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir), and nefazodone is contraindicated (see section «Contraindications»). Such strong CYP3A4 inhibitors as ketoconazole (200 mg daily) and josamycin (1 g twice daily) increase the average plasma concentration of ivabradine by 7–8 times.

Moderate CYP3A4 inhibitors

Specific studies in patients have shown that combining ivabradine with heart rate-lowering agents such as diltiazem and verapamil leads to increased plasma concentration of ivabradine (2–3 times in terms of AUC) and additional reduction in heart rate by 5 bpm. Concomitant use of ivabradine with these medicinal products is contraindicated (see section «Contraindications»).

Not recommended combinations

Concomitant intake of grapefruit juice and ivabradine doubles the latter's plasma concentration. Therefore, consumption of grapefruit juice should be avoided.

Combinations requiring caution in use

Moderate CYP3A4 inhibitors (e.g., fluconazole)
Concomitant use of ivabradine with other moderate CYP3A4 inhibitors (e.g., fluconazole) may be initiated at a dose of 2.5 mg twice daily if the resting heart rate is > 70 bpm. Heart rate should be monitored.

CYP3A4 inducers

• CYP3A4 inducers (rifampicin, barbiturates, phenytoin, St. John’s wort [Hypericum perforatum])

Concomitant use of these agents with ivabradine may lead to reduced plasma concentrations of ivabradine and decreased efficacy, necessitating dose adjustment. When ivabradine 10 mg twice daily is used concomitantly with St. John’s wort, ivabradine concentration is reduced by half. Therefore, use of St. John’s wort should be avoided during treatment with ivabradine.

Other combinations

No clinically significant effect on the pharmacokinetics and pharmacodynamics of ivabradine has been reported with the following medicinal products: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin, and warfarin. It has been demonstrated that ivabradine does not exert clinically significant effects on the pharmacokinetics of simvastatin, amlodipine, lacidipine, or on the pharmacokinetics and pharmacodynamics of digoxin and warfarin, nor on the pharmacodynamics of aspirin.

The possibility of using ivabradine concomitantly with angiotensin-converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, aldosterone antagonists, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetic agents, aspirin, and other antithrombotic agents has been confirmed.

Special precautions.

Special warnings

Insufficient beneficial effect on clinical outcomes in patients with symptomatic chronic stable angina

Ivabradine is indicated only for symptomatic treatment of chronic stable angina, as treatment with ivabradine has not demonstrated a reduction in the risk of cardiovascular complications such as myocardial infarction or cardiovascular death (see section "Pharmacodynamics").

Heart rate measurement

Due to possible significant fluctuations in heart rate (HR), HR should be measured at rest before initiating treatment. If dose titration of ivabradine is required, serial HR measurements, ECG, or 24-hour ambulatory monitoring should be performed. This also applies to patients with low HR, particularly if HR decreases to < 50 beats/min, or after dose reduction (see section "Dosage and administration").

Arrhythmias

Ivabradine should not be prescribed for the prevention or treatment of arrhythmias. If tachyarrhythmia (ventricular or supraventricular) develops during ivabradine therapy, continued administration of ivabradine is no longer appropriate. Therefore, ivabradine is not recommended for patients with atrial fibrillation or other types of arrhythmias affecting sinus node function.

The risk of developing atrial fibrillation is increased in patients taking ivabradine (see section "Adverse reactions"). Atrial fibrillation occurs more frequently in patients who are concurrently using amiodarone or potent Class I antiarrhythmic drugs. During treatment with ivabradine, regular clinical monitoring is recommended to enable timely diagnosis of atrial fibrillation (paroxysmal or persistent), including ECG if clinically justified (worsening angina symptoms, palpitations, irregular pulse). Patients should be informed about symptoms of atrial fibrillation and advised to notify their physician if such symptoms occur. If atrial fibrillation develops during treatment, the benefit-risk balance should be carefully evaluated before continuing ivabradine therapy.

Patients with heart failure (HF), intraventricular conduction disturbances (left bundle branch block, right bundle branch block), and ventricular dyssynchrony should be under close monitoring.

Patients with Second-degree AV block

Ivabradine is not recommended for such patients.

Patients with low heart rate

Ivabradine should not be prescribed to patients whose resting heart rate before treatment initiation is < 70 beats/min (see section "Contraindications"). If during therapy the resting HR decreases to < 50 beats/min or if symptoms of bradycardia (dizziness, weakness, hypotension) occur, the dose should be gradually reduced or treatment discontinued if HR remains < 50 beats/min or bradycardia symptoms persist (see section "Dosage and administration").

Combination with calcium channel blockers

Concomitant use of ivabradine with calcium channel blockers that reduce heart rate, such as verapamil or diltiazem, is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). No safety concerns have been reported with the use of ivabradine together with short- or long-acting nitrates or dihydropyridine calcium channel blockers (e.g., amlodipine). Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been studied (see section "Pharmacodynamics").

Chronic heart failure

When deciding to initiate ivabradine therapy in heart failure, the patient's condition should be assessed. Treatment is only possible if heart failure is stable. Ivabradine should be used with caution in patients with NYHA class IV heart failure due to limited data available for this patient group.

Stroke

Ivabradine is not recommended for immediate use in patients following a stroke, as studies involving this patient group have not been conducted.

Ocular effects

There is evidence that ivabradine affects retinal function. There is no evidence of retinal toxicity with long-term use of ivabradine (see section "Pharmacodynamics"). If any unexpected visual disturbances occur, treatment should be discontinued. Ivabradine should be prescribed with caution in patients with retinitis pigmentosa.

Patients with arterial hypotension

Due to insufficient data on the use of ivabradine in patients with mild to moderate arterial hypotension, it should be used with caution in such patients. Ivabradine is contraindicated in patients with severe arterial hypotension (BP < 90/50 mm Hg) (see section "Contraindications").

Atrial fibrillation – cardioversion

There is no evidence of risk of severe bradycardia upon restoration of sinus rhythm during pharmacological cardioversion in patients treated with ivabradine. However, due to insufficient data, non-emergency DC cardioversion is recommended to be performed no sooner than 24 hours after the last dose of ivabradine.

Patients with congenital long QT syndrome or taking drugs that prolong the QT interval

Such patients should avoid using ivabradine (see section "Interaction with other medicinal products and other forms of interaction"). If ivabradine must be prescribed to these patients, careful cardiological monitoring is recommended. Heart rate reduction due to ivabradine may exacerbate QT interval prolongation, which is associated with the risk of severe arrhythmias, particularly torsades de pointes.

Patients with arterial hypertension requiring changes in therapy

In patients treated with ivabradine, more episodes of increased blood pressure (7.1%) were observed compared to placebo-treated patients (6.1%). These episodes occurred more frequently shortly after changes in antihypertensive therapy, were transient, and did not affect the therapeutic effect of ivabradine. Blood pressure should be monitored at regular intervals when changes in therapy are introduced in patients with chronic heart failure during ivabradine treatment (see section "Adverse reactions").

Excipients. The product contains lactose; therefore, it should not be administered to patients with congenital galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency.

Use during pregnancy or breastfeeding.

Women of childbearing potential

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

Pregnancy

Data on the use of ivabradine in pregnant women are lacking or limited. Animal studies have shown toxic effects of ivabradine on reproductive function, as well as embryotoxic and teratogenic effects. The potential risk in humans is unknown. Therefore, the use of ivabradine during pregnancy is contraindicated (see section "Contraindications").

Breastfeeding

Animal studies have demonstrated that ivabradine passes into breast milk. Therefore, the use of ivabradine during breastfeeding is contraindicated.

Women requiring ivabradine treatment should discontinue breastfeeding and choose an alternative method of infant feeding.

Fertility

Animal studies showed no effect of ivabradine on fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

A specific study evaluating the potential effect of ivabradine on driving ability, conducted in healthy volunteers, showed no changes in driving performance. However, post-marketing experience has reported cases of impaired driving ability due to visual phenomena. Ivabradine may cause transient visual phenomena, mostly in the form of phosphenes (see section "Adverse reactions"). The possible occurrence of such visual phenomena should be considered when driving or operating machinery, particularly in situations involving sudden changes in light intensity, especially during night driving.

Ivabradine has no effect or a negligible effect on the ability to operate machinery.

Method of Administration and Dosage

Bravadin® should be prescribed to adults.

The tablets should be taken orally twice daily: in the morning and in the evening with meals (see section "Pharmacokinetics").

The Bravadin® 5 mg tablet may be divided into equal doses.

The Bravadin® 7.5 mg tablet must not be divided.

Symptomatic treatment of chronic stable angina

Decisions regarding initiation of treatment or dose titration are recommended to be based on results of serial measurements of heart rate (HR), ECG, or 24-hour ambulatory monitoring.

For patients under 75 years of age, the initial dose of ivabradine should not exceed 5 mg twice daily. If symptoms of stable angina persist after 3–4 weeks of treatment in patients receiving ivabradine 2.5 mg or 5 mg twice daily, the dose may be increased, provided the initial dose is well tolerated and resting heart rate remains > 60 beats per minute (bpm). The maintenance dose should not exceed 7.5 mg twice daily.

If no reduction in angina symptoms is observed within 3 months after initiation of treatment, ivabradine therapy should be discontinued.

Furthermore, the continuation of therapy should be reconsidered if symptomatic response is minimal and there is no clinically significant reduction in resting heart rate during 3 months of treatment.

If during treatment the resting heart rate decreases to < 50 bpm or if the patient develops symptoms of bradycardia (dizziness, weakness, arterial hypotension), the dose should be gradually reduced, including the possibility of using the lowest dose of 2.5 mg twice daily (½ of Bravadin® 5 mg tablet twice daily). Heart rate should be monitored after dose reduction (see section "Special precautions"). The drug should be discontinued if heart rate remains < 50 bpm or if bradycardia symptoms persist despite dose reduction.

Treatment of chronic heart failure

Treatment may be initiated only in patients with stable chronic heart failure (CHF), under the supervision of a physician experienced in the management of CHF.

The recommended initial dose of ivabradine is 5 mg twice daily. After a two-week treatment period, the dose may be increased to 7.5 mg twice daily if the resting heart rate remains > 60 bpm during treatment; or the dose should be reduced to 2.5 mg twice daily (½ of Bravadin® 5 mg tablet twice daily) if the resting heart rate remains < 50 bpm or if the patient develops symptoms of bradycardia (dizziness, weakness, arterial hypotension). If the heart rate is within the range of 50–60 bpm, the dose of ivabradine 5 mg twice daily should be maintained unchanged.

If during treatment the resting heart rate decreases to < 50 bpm or if symptoms of bradycardia occur while receiving ivabradine 7.5 mg or 5 mg twice daily, the dose should be gradually reduced to the next lower level. If the resting heart rate remains persistently > 60 bpm, patients receiving ivabradine 2.5 mg or 5 mg twice daily should have their dose gradually increased to the next higher level.

Treatment with the drug should be discontinued if during therapy the heart rate remains < 50 bpm or if bradycardia symptoms persist (see section "Special precautions").

Special patient groups

Elderly patients

For patients aged 75 years and older, treatment should be initiated with a lower starting dose (2.5 mg twice daily, i.e., ½ of Bravadin® 5 mg tablet twice daily). The dose may be gradually increased if further reduction of heart rate is required.

Patients with renal impairment

Patients with creatinine clearance > 15 ml/min do not require dose adjustment (see section "Pharmacokinetics"). Due to insufficient data, ivabradine should be used with caution in patients with creatinine clearance < 15 ml/min.

Patients with hepatic impairment

Patients with mild hepatic impairment do not require dose adjustment. Ivabradine should be used with caution in patients with moderate hepatic impairment. Ivabradine is contraindicated in patients with severe hepatic impairment due to the lack of studies in this patient group and the potential for a marked increase in drug concentration in blood (see sections "Pharmacokinetics" and "Contraindications").

Children

The safety and efficacy of ivabradine in children (< 18 years of age) have not been established.

There are insufficient data on the treatment of chronic heart failure described in the sections "Pharmacodynamics" and "Pharmacokinetics" to recommend a dosing regimen. There are no data on the symptomatic treatment of chronic stable angina in this population.

Overdose

Overdose with ivabradine may lead to severe and prolonged bradycardia (see section "Adverse reactions"). Severe forms of bradycardia require symptomatic treatment in specialized facilities. In case of bradycardia with hemodynamic compromise, intravenous beta-stimulating agents such as isoprenaline are recommended. In extremely severe cases, temporary use of a cardiac pacemaker may be considered.

Adverse reactions

The most common adverse reactions with ivabradine are visual phenomena (phosphenes) (14.5%) and bradycardia (3.3%), which are dose-dependent and related to its pharmacological mechanism of action.

The following adverse reactions may occur during treatment with the medicinal product, categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10,000, < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Blood and lymphatic system disorders. Uncommon: eosinophilia.

Metabolism and nutrition disorders. Uncommon: increased plasma uric acid levels.

Nervous system disorders. Common: headache, usually during the first month of treatment; dizziness, likely related to bradycardia. Uncommon*: syncope, likely related to bradycardia.

Eye disorders. Very common: visual phenomena (phosphenes). Common: blurred vision. Uncommon*: diplopia, visual disturbances.

Ear and labyrinth disorders. Uncommon: vertigo.

Cardiac disorders. Common: bradycardia; first-degree AV block (on ECG – prolonged PQ interval); ventricular extrasystoles; atrial fibrillation. Uncommon: palpitations, supraventricular extrasystoles. Very rare: second- and third-degree AV block; sick sinus syndrome.

Vascular disorders. Common: uncontrolled blood pressure. Uncommon*: arterial hypotension, likely related to bradycardia.

Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnoea.

Gastrointestinal disorders. Uncommon: nausea, constipation, diarrhoea, abdominal pain*.

Skin and subcutaneous tissue disorders. Uncommon*: angioedema; rash. Rare*: erythema, pruritus, urticaria.

Musculoskeletal and connective tissue disorders. Uncommon: muscle spasms.

Renal and urinary disorders. Uncommon: increased plasma creatinine levels.

General disorders. Uncommon*: asthenia, likely related to bradycardia; fatigue, likely related to bradycardia. Rare*: malaise, likely related to bradycardia.

Investigations. Uncommon: QT interval prolongation on ECG.

*Frequency of adverse reactions identified from spontaneous reports was calculated based on clinical trial data.

Description of selected adverse reactions

Visual phenomena (phosphenes) were observed in 14.5% of patients as a temporary increase in brightness within a limited area of the visual field. These usually occur in response to sudden changes in light intensity. Phosphenes have also been described as halos, image decomposition (stroboscopic and kaleidoscopic effects), bright colored flashes, or multiple images (retinal persistence). Phosphenes occur mainly during the first two months of treatment and may recur later. Most cases were reported as mild or moderate in intensity. All phosphenes resolved either during treatment or after discontinuation, with the majority (77.5%) resolving during therapy. Less than 1% of patients required modification of daily activities or discontinuation of treatment due to phosphenes.

Bradycardia was observed in 3.3% of patients, particularly during the first 2–3 months after initiation of treatment. Severe bradycardia with heart rate ≤ 40 beats per minute occurred in 0.5% of patients.

Atrial fibrillation was observed in 5.3% of patients treated with ivabradine, compared to 3.8% in the placebo group.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

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Shelf life. 3 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging.

14 tablets per blister; 2, 4, or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.