Coraxan® 5 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Coraxan® 5 mg (Coraxan® 5 mg) Coraxan® 7.5 mg (Coraxan® 7.5 mg)

Composition:

Active substance: ivabradine;

1 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;

Film coating: glycerin, hypromellose, iron oxide yellow (E 172), iron oxide red (E 172), macrogol 6000, magnesium stearate, titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Coraxan® 5 mg: orange-pink, film-coated, elongated tablet with notches on both sides and engraved with "5" on one side and "" on the other.

Coraxan® 7.5 mg: orange-pink, film-coated, triangular-shaped tablet engraved with "7.5" on one side and "" on the other.

Pharmacotherapeutic group. Cardiological agents. Other cardiological agents.
ATC code C01EB17.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Ivabradine is a substance that selectively 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, thereby regulating 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 Ih channels in the retina, which are structurally similar to the I_f channels 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 change in lighting), partial inhibition of Ih channels by ivabradine may lead to unexpected visual phenomena in patients. Visual phenomena (phosphenes) are described as a transient increase in brightness within 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/min (see section "Adverse Reactions").

At recommended therapeutic doses (5–7.5 mg twice daily), ivabradine reduces HR by approximately 10 beats/min 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

The antianginal and anti-ischemic efficacy of ivabradine has been demonstrated in five double-blind, randomized trials (three compared with placebo, one with atenolol, and one with amlodipine). A total of 4111 patients with chronic stable angina participated in these studies, of whom 2617 received ivabradine.

Ivabradine at a dose of 5 mg twice daily demonstrated efficacy in exercise testing parameters after 3–4 weeks of treatment. Additional benefits of increasing the dose to 7.5 mg twice daily were demonstrated in a controlled comparative study with atenolol: exercise test duration increased by 1 minute after one month of treatment with ivabradine 5 mg twice daily; after three months of dose escalation to 7.5 mg twice daily, exercise duration further increased by almost 25 seconds. In this study, the antianginal and anti-ischemic properties of ivabradine were confirmed in patients aged ≥ 65 years. Efficacy of ivabradine at doses of 5 and 7.5 mg twice daily was consistent across all studies in exercise testing parameters (total exercise duration, time to 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, effective action over 24 hours.

In a randomized, placebo-controlled study involving 889 patients, ivabradine administered in addition to atenolol 50 mg once daily showed additional efficacy in all exercise test parameters at the interdose interval (12 hours post-dose).

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

A 1-year study involving 713 patients confirmed the sustained effect of ivabradine on HR reduction and demonstrated no effect on glucose and lipid metabolism.

Anti-ischemic and antianginal efficacy and safety of ivabradine were confirmed in patients with diabetes (n = 457).

In the large-scale BEAUTIFUL study on morbidity and mortality involving 10,917 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 β-blockers). The primary efficacy endpoint (primary composite endpoint) was the total number of cardiovascular deaths, hospitalizations due to myocardial infarction (MI), and hospitalizations for onset or worsening of heart failure (HF). The study showed no significant difference in reduction of the primary composite endpoint between ivabradine and placebo groups, either in the overall population (relative risk [RR] 1.00; p = 0.94) or in the subgroup analysis of patients with HR ≥ 70 beats/min (RR 0.91; p = 0.17). However, in the group of patients with HR ≥ 70 beats/min receiving ivabradine, the rate of hospitalizations due to fatal and non-fatal MI decreased by 36% (p = 0.001), and coronary revascularization procedures decreased by 30% (p = 0.016).

A subgroup analysis in patients with symptomatic angina (n = 1507) showed a 24% reduction in the primary endpoint in the ivabradine group (p = 0.05). This benefit was primarily driven by a significant reduction in hospitalizations due to MI (42%; p = 0.021). The reduction in hospitalizations due to fatal and non-fatal MI was even more pronounced (73%; p = 0.002) in patients with angina-limiting symptoms and HR ≥ 70 beats/min.

In the large-scale SIGNIFY study on morbidity and mortality involving 19,102 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 dosing regimen than approved was used (initial dose: 7.5 mg twice daily [5 mg twice daily for patients over 75 years], with dose titration up to 10 mg twice daily). The primary efficacy endpoint was the composite primary endpoint consisting of total cardiovascular deaths or non-fatal myocardial infarction. The study found no difference in the rate of the composite primary endpoint between ivabradine and placebo groups (RR 1.08; p = 0.197). Bradycardia was observed in 17.9% of ivabradine-treated patients (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 rate of the composite primary endpoint was observed in a pre-specified subgroup of patients with CCS class II or higher angina (Canadian Cardiovascular Society classification) (n = 12,049) (3.4% per year vs. 2.9%, RR 1.18; p = 0.018); however, no such effect was observed in the overall population of patients with CCS class ≥ I angina (n = 14,286) (RR 1.11; p = 0.110).

The use of higher-than-approved doses in the study partially explains these results.

SHIFT was a multicenter, international, randomized, double-blind, placebo-controlled morbidity and mortality study involving 6,505 adult patients with stable chronic heart failure (CHF) and left ventricular dysfunction (LVEF ≤ 35%). The study included patients with systolic CHF of NYHA functional class II–IV (New York Heart Association classification), duration ≥ 4 weeks, and resting HR ≥ 70 beats/min.

Patients received standard therapy, including β-blockers (89%), ACE 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. Median follow-up was 22.9 months. Ivabradine treatment was associated with an average HR reduction of 15 beats/min compared to a baseline of 80 beats/min. The difference in HR between ivabradine and placebo groups was 10.8 beats/min after 28 days, 9.1 beats/min at 12 months, and 8.3 beats/min at 24 months.

This study demonstrated a clinically and statistically significant 18% reduction in the rate of the composite primary endpoint (cardiovascular death and hospitalization for worsening CHF) (RR 0.82, 95% confidence interval [CI] 0.75–0.90; p < 0.0001). Absolute risk reduction was 4.2%. The treatment effect with ivabradine was evident within the first 3 months of therapy. The results of the composite primary endpoint were primarily driven by endpoints related to heart failure, including hospitalizations for worsening CHF (absolute risk reduction 4.7%) and deaths due to CHF (absolute risk reduction 1.1%).

Impact of ivabradine therapy on the composite primary endpoint, its components, and secondary endpoints

	Ivabradine (N = 3241) n (%)	Placebo (N = 3264) n (%)	HR (95 % CI)	p-value
Primary composite endpoint	793 (24.47)	937 (28.71)	0.82 (0.75–0.90)	< 0.0001
Components of primary endpoint: cardiovascular death; hospitalization for worsening heart failure	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: death from any cause; death due to heart failure; hospitalizations for any cause; hospitalizations for cardiovascular disease	503 (15.52) 113 (3.49) 1231 (37.98) 977 (30.15)	552 (16.91) 151 (4.63) 1356 (41.54) 1122 (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

A reduction in the incidence of the combined primary endpoint was observed independently of sex, NYHA class, ischemic or non-ischemic etiology of heart failure, and the presence of concomitant diseases (diabetes mellitus or arterial hypertension) in the patient's medical history.

In the subgroup of patients with resting heart rate ≥ 75 beats/min (n = 4150), a significant 24% reduction in the incidence of the primary endpoint was observed (HR 0.76, 95% CI 0.68–0.85; p < 0.0001), as well as in other secondary endpoints, including all-cause mortality (HR 0.83, 95% CI 0.72–0.96; p < 0.0109) and cardiovascular death (HR 0.83, 95% CI 0.71–0.97; p < 0.0166). The safety profile of ivabradine in this subgroup was consistent with that observed in the overall population.

This study demonstrated a significant reduction in the incidence of the combined primary endpoint in the overall group of patients receiving β-blocker therapy (HR 0.85, 95% CI 0.76–0.94). In the subgroup of patients with resting heart rate ≥ 75 beats/min receiving β-blockers at recommended doses, no statistically significant effect was observed on the combined primary endpoint (HR 0.97, 95% CI 0.74–1.28) or other secondary endpoints, including hospitalization due to worsening heart failure (HR 0.79, 95% CI 0.56–1.10) or death due to heart failure (HR 0.69, 95% CI 0.31–1.53).

Functional class improvement (according to NYHA classification) was observed in 887 (28%) patients in the ivabradine group compared to 776 (24%) in the placebo group (p = 0.001).

In a randomized, placebo-controlled study involving 97 patients, specialized ophthalmological assessments—designed to document the function of cone and rod systems and the ascending visual pathway (via electroretinography, static and kinetic visual field testing, color vision, and visual acuity)—performed in patients treated with ivabradine for chronic stable angina over 3 years did not reveal any retinal toxicity.

Pharmacokinetics.

Under physiological conditions, ivabradine is rapidly released and highly water-soluble (> 10 mg/mL). Ivabradine is the S-enantiomer and has shown no in vivo bioconversion. 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 on an empty stomach, maximum plasma concentration (Cmax) is reached within approximately 1 hour. The absolute bioavailability of ivabradine is nearly 40%, due to first-pass metabolism in the gut and liver. Administration with food delays absorption by approximately 1 hour and increases plasma concentration by 20–30%. To minimize intra-individual fluctuations in plasma concentration, ivabradine should 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 prolonged administration of the recommended initial dose of 5 mg twice daily, the Cmax 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 concentrations reaching 40% of those 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 is therefore unlikely to alter CYP3A4 metabolism or plasma concentrations of other drugs. However, CYP3A4 inhibitors and inducers can significantly affect ivabradine plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

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

Linearity/non-linearity. The pharmacokinetics of ivabradine are linear over the dose range of 0.5–24 mg.

Special patient populations.

Elderly patients (65–75 years): pharmacokinetic parameters (AUC and Cmax) in this age group do not differ significantly from those in the general patient population.

Renal impairment: The effect of renal impairment (creatinine clearance 15–60 mL/min) on ivabradine kinetics is minimal due to the small contribution of renal clearance (approximately 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, unbound AUC values for ivabradine and its main active metabolite were 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 "Dosage and administration" and "Contraindications").

Pharmacokinetic/pharmacodynamic relationship. Analysis of the pharmacokinetic/pharmacodynamic relationship demonstrated a linear correlation between decreasing heart rate and increasing plasma concentrations of ivabradine and its active metabolite at doses of 15–20 mg twice daily. At higher doses, the reduction in heart rate 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 a marked decrease in heart rate; however, the risk is reduced when ivabradine is used with moderate CYP3A4 inhibitors (see sections "Contraindications", "Special precautions", and "Interaction with other medicinal products and other forms of interaction").

Clinical characteristics.

Indications.

Symptomatic treatment of chronic stable angina.

Coraxan® is indicated for the symptomatic treatment of chronic stable angina in adult patients with ischemic heart disease, normal sinus rhythm, and heart rate ≥ 70 beats/min. The drug should be prescribed:

• to patients who have contraindications or limitations to the use of β-adrenergic blockers;
• in combination with β-adrenergic blockers to patients whose condition is insufficiently controlled with optimal doses of β-adrenergic blockers.

Treatment of chronic heart failure.

Reduction of the risk of cardiovascular events (cardiovascular death or hospitalization due to worsening heart failure) in adult patients with symptomatic chronic heart failure, sinus rhythm, and heart rate ≥ 70 beats/min.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.

• Resting heart rate < 70 beats/min before initiation of treatment.

• Cardiogenic shock.

• Acute myocardial infarction.

• Severe arterial hypotension (BP < 90/50 mmHg).

• Severe hepatic impairment.

• Sick sinus syndrome.

• Sinoatrial block.

• Unstable or acute heart failure.

• Presence of a cardiac pacemaker in the patient (heart rate controlled exclusively by a cardiac pacemaker).

• Unstable angina.

• Third-degree AV block.

• Combination with strong P450 3A4 inhibitors: antifungal agents – azole derivatives (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir), and nefazodone (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacokinetics").

• 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, and women of childbearing potential who do not use appropriate contraceptive methods (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 precautions during use.

Diuretics (thiazide and loop diuretics). Hypokalemia may increase the risk of arrhythmia. Ivabradine may cause bradycardia, and its combination with hypokalemia may trigger severe arrhythmia, particularly in patients with long QT syndrome, whether congenital or drug-induced.

Pharmacokinetic interactions.

Cytochrome P450 3A4 (CYP3A4). 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 or plasma concentrations of other CYP3A4 substrates (weak, moderate, or strong). Inhibitors and inducers of CYP3A4 are prone to interact with ivabradine, resulting in clinically significant effects on its metabolism and pharmacokinetics. Drug interaction studies have confirmed that CYP3A4 inhibitors increase plasma concentrations of ivabradine, while CYP3A4 inducers decrease them. Increased plasma concentrations of ivabradine may increase the risk of excessive bradycardia (see section "Special precautions for use").

Contraindicated combinations.

Concomitant administration 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"). Strong CYP3A4 inhibitors such as ketoconazole (200 mg/day) and josamycin (1 g twice daily) increase the average plasma concentration of ivabradine by 7–8 times.

Moderate CYP3A4 inhibitors. Specific studies in healthy volunteers and patients have shown that combining ivabradine with heart rate-lowering agents such as diltiazem and verapamil leads to increased ivabradine concentrations (2–3-fold increase in AUC) and additional reduction in heart rate by 5 beats/min. Concomitant use of ivabradine with these medicinal products is contraindicated (see section "Contraindications").

Not recommended combinations.

Grapefruit juice. Concurrent intake of grapefruit juice and ivabradine doubles the plasma concentration of the latter. Therefore, consumption of grapefruit juice should be avoided.

Combinations requiring precautions during use.

Other moderate CYP3A4 inhibitors (e.g., fluconazole). Concomitant use with ivabradine may be initiated at a dose of 2.5 mg twice daily if resting heart rate is > 70 beats/min. Heart rate monitoring is required.

CYP3A4 inducers – rifampicin, barbiturates, phenytoin, St. John’s wort (Hypericum perforatum). Concomitant use of these agents with ivabradine may reduce its plasma concentration and efficacy, necessitating dose adjustment of ivabradine. When ivabradine 10 mg twice daily is co-administered with St. John’s wort, ivabradine concentration is halved. Therefore, the use of St. John’s wort should be avoided during treatment with ivabradine.

Other combinations.

Specific drug interaction studies have shown no clinically significant effect on the pharmacokinetics and pharmacodynamics of ivabradine by the following medicinal products: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin, and warfarin. Studies have also demonstrated that ivabradine does not exert any clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, or on the pharmacokinetics and pharmacodynamics of digoxin and warfarin, or on the pharmacodynamics of aspirin.

Phase III clinical trials have confirmed the possibility of using ivabradine in combination with ACE inhibitors, angiotensin II antagonists, β-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.

Special precautions for use.

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, since treatment with ivabradine has not demonstrated a beneficial effect on reducing the risk of cardiovascular events (such as myocardial infarction or cardiovascular death) (see section "Pharmacodynamics").

Heart rate measurement. Due to the possibility of significant fluctuations in heart rate (HR), serial HR measurements, ECG, or 24-hour ambulatory monitoring should be performed when determining resting HR before initiating treatment and when dose titration is required in patients taking ivabradine. This also applies to patients with low HR, especially if HR decreases to < 50 bpm, or after dose reduction (see section "Dosage and administration").

Arrhythmias. Ivabradine is not prescribed for the prevention or treatment of arrhythmias. If a tachyarrhythmia (ventricular or supraventricular) develops in a patient during ivabradine therapy, continuing ivabradine treatment is no longer appropriate. Therefore, ivabradine is not recommended for patients with atrial fibrillation and other types of arrhythmias affecting sinus node function.

Patients receiving ivabradine have an increased risk of developing atrial fibrillation (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 of patients is recommended to enable timely diagnosis of atrial fibrillation (paroxysmal or persistent), including ECG monitoring if clinically justified (worsening angina symptoms, palpitations, irregular pulse). Patients should be informed about the signs and symptoms of atrial fibrillation and advised to report them to their physician promptly. If atrial fibrillation develops during treatment, the continuation of ivabradine therapy should be carefully reconsidered based on benefit-risk assessment.

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

Patients with second-degree AV block. Ivabradine is not recommended for these patients.

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

Combination with calcium channel blockers. Concomitant use of ivabradine with calcium channel blockers that reduce HR, such as verapamil or diltiazem, is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction"). There have been no reports of danger associated with using ivabradine together with short- or long-acting nitrates or dihydropyridine calcium channel blockers (e.g., amlodipine). The 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 must be assessed. Treatment is possible only if heart failure is stable. Ivabradine should be used with caution in patients with NYHA class IV heart failure due to limited data in this population.

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

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

Precautionary measures during use.

Patients with arterial hypotension. Due to insufficient data on the use of ivabradine in patients with mild to moderate arterial hypotension, the drug 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. Cardiac arrhythmias. There is no evidence of risk for severe bradycardia upon restoration of sinus rhythm after pharmacological cardioversion in patients treated with ivabradine. However, due to insufficient data, non-emergency DC cardioversion should be performed no earlier than 24 hours after the last dose of ivabradine.

Patients with congenital long QT syndrome or those taking drugs that prolong the QT interval. These patients should avoid using ivabradine (see section "Interaction with other medicinal products and other forms of interaction"). If ivabradine must be prescribed to such patients, careful cardiac monitoring is recommended. HR reduction caused by ivabradine may exacerbate QT interval prolongation, which is associated with the risk of severe arrhythmias, particularly torsades de pointes.

Patients with arterial hypertension requiring treatment adjustments. In the SHIFT study, more episodes of increased BP (7.1%) were observed in patients taking ivabradine compared to those on placebo (6.1%). These episodes occurred more frequently shortly after changes in antihypertensive therapy, were transient, and did not affect the therapeutic effect of ivabradine. When treatment modifications are introduced in patients with chronic heart failure during ivabradine therapy, BP should be monitored at regular intervals (see section "Adverse reactions").

Excipients. The drug contains lactose; therefore, it should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Women of childbearing potential. Women of childbearing potential should use appropriate contraceptive methods during treatment.

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.

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

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

Fertility. Studies in rats have shown no effect of ivabradine on fertility in males or females.

Ability to affect reaction speed when driving or operating machinery.

A targeted study in healthy volunteers demonstrated that ivabradine does not impair the ability to drive or operate machinery. However, during the post-marketing period, cases of impaired driving ability due to visual symptoms have been reported. Ivabradine may cause transient visual phenomena, mostly phosphenes, typically occurring in response to sudden changes in light intensity. This should be taken into account when driving, especially at night, and when operating machinery.

Method of Administration and Dosage.

Coraxan® is intended for adults.

The tablets are taken orally twice daily: in the morning and in the evening with meals.

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

The 7.5 mg Coraxan® tablet must not be divided.

Symptomatic treatment of chronic stable angina.

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

In 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 or 5 mg twice daily, the dose may be increased to the next level, 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 there is no improvement in angina symptoms within 3 months after initiation of treatment, ivabradine therapy should be discontinued.

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

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

Treatment of chronic heart failure.

Treatment should only be initiated in patients with stable heart failure by a physician experienced in managing chronic heart failure (CHF).

The recommended initial dose of ivabradine is 5 mg twice daily. After a 2-week treatment period, the dose may be increased to 7.5 mg twice daily if the heart rate remains > 60 bpm at rest during treatment; or the dose should be reduced to 2.5 mg twice daily (½ of a Coraxan® 5 mg tablet twice daily) if the heart rate remains < 50 bpm at rest or if the patient experiences symptoms related to bradycardia (dizziness, weakness, 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 heart rate decreases to < 50 bpm at rest or the patient experiences symptoms of bradycardia while receiving ivabradine 7.5 or 5 mg twice daily, the dose should be gradually reduced to the next lower level. If the resting heart rate remains consistently > 60 bpm, patients receiving ivabradine 2.5 or 5 mg twice daily should have their dose gradually increased to the next higher level.

The drug should be discontinued if the heart rate remains < 50 bpm during treatment or if symptoms of bradycardia persist (see section "Special Instructions").

Special patient populations.

Elderly patients. In patients aged 75 years and older, treatment should be initiated with a lower starting dose (2.5 mg twice daily, i.e., ½ of a Coraxan® 5 mg tablet twice daily). If further reduction of heart rate is needed, the dose may be gradually increased.

Renal impairment. Patients with a 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.

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 significant increase in drug plasma concentration (see sections "Contraindications" and "Pharmacokinetics").

Children.

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

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 β-stimulating agents such as isoprenaline are recommended. In extremely severe cases, temporary use of a cardiac pacemaker may be considered.

Adverse reactions.

Ivabradine has been studied in clinical trials involving approximately 45,000 individuals.

The most common adverse reactions associated with ivabradine – visual phenomena (phosphenes) and bradycardia – 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 (≥ 1/10000, < 1/1000); very rare (< 1/10000); 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 disturbance.

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: dyspnea.

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

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

Musculoskeletal and connective tissue disorders. Uncommon: muscle spasms.

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

Investigations. Uncommon: increased plasma creatinine levels; QT interval prolongation on ECG.

* Frequency of adverse reactions identified from spontaneous reports, calculated based on data from clinical trials.

Description of selected adverse reactions.

Visual phenomena (phosphenes) were observed in 14.5% of patients as transient increases in brightness within a limited area of the visual field. Their occurrence is usually triggered by a sudden change 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 predominantly 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 its discontinuation, with the majority (77.5%) resolving during therapy. Less than 1% of patients required changes in their usual 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/min occurred in 0.5% of patients.

In the SIGNIFY trial, atrial fibrillation was observed in 5.3% of patients receiving ivabradine compared to 3.8% of patients in the placebo group. A pooled analysis of results from all double-blind, placebo-controlled Phase II and III clinical trials of at least 3 months’ duration involving more than 40,000 patients demonstrated that the incidence of atrial fibrillation was 4.86% in patients receiving ivabradine compared to 4.08% in the placebo group, corresponding to a relative risk of 1.26 (95% confidence interval: 1.15–1.39).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse effects through the national reporting system.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of the reach and sight of children.

Packaging.

14 tablets in a blister pack made of aluminum foil and PVC film; 2 or 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Les Laboratoires Servier Industrie / Les Laboratoires Servier Industrie.

Manufacturer's address.

905 route de Saran, 45520 Gidy, France / 905 route de Saran, 45520 Gidy, France.

Manufacturer.

Servier (Ireland) Industries Ltd / Servier (Ireland) Industries Ltd.

Manufacturer's address.

Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland / Moneylands, Gorey Road, Arklow, Co. Wicklow, Ireland.

Marketing Authorization Holder.

Les Laboratoires Servier / Les Laboratoires Servier.

Address of Marketing Authorization Holder.

50, rue Carnot, 92284 Suresnes Cedex, France / 50, rue Carnot, 92284 Suresnes Cedex, France.

For any information regarding the medicinal product, please contact LLC "Servier Ukraine" at tel. (044) 490 3441, fax: (044) 490 3440.