Raenom

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

Composition:

Active substance: ivabradine (as ivabradine hydrobromide);

1 film-coated tablet contains 5 mg of ivabradine, equivalent to 5.863 mg of ivabradine hydrobromide, or

1 film-coated tablet contains 7.5 mg of ivabradine, equivalent to 8.795 mg of ivabradine hydrobromide;

Excipients: lactose, mannitol (E 421), maltodextrin, sodium croscarmellose, colloidal anhydrous silicon dioxide (E 551), magnesium stearate;

Film coating: polyvinyl alcohol (E 1203), talc (E 553b), titanium dioxide (E 171), macrogol/PEG 3350 (E 1521), methacrylic acid copolymer (1:1), yellow iron oxide (E 172), red iron oxide (E 172), sodium bicarbonate (E 500).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets:

light-orange, oval, biconvex, film-coated tablets, engraved with «CK3» on one side and a line on the other. Size ~ 8.6 mm × 4.5 mm;

7.5 mg tablets:

light-orange, round, biconvex, film-coated tablets, engraved with «CK4» on one side, the other side unmarked. Diameter ~ 6 mm.

Pharmacotherapeutic group. Cardiological agents. Other cardiological agents.

ATC code C01EB17.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Ivabradine is a substance that exclusively reduces heart rate by acting on the cardiac pacemaker through selective and specific inhibition of the If channel, which controls spontaneous diastolic depolarization at the level of the sinus node, thereby regulating heart rate. 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 channel in the retinal tissue, which is structurally similar to the If channel in the cardiac sinus node. This interaction underlies the development of transient disturbances in light perception due to reduced retinal response to bright light stimuli. Under triggering conditions (e.g., sudden changes in lighting), partial inhibition of the Ih channel by ivabradine may lead to visual phenomena in patients. Visual phenomena (phosphenes) are described as transient increases in brightness within a limited area of the visual field (see section "Adverse Reactions").

Pharmacodynamic effects.

The main pharmacodynamic property of ivabradine is its specific, dose-dependent reduction in heart rate (HR). Analysis of HR reduction with doses up to 20 mg twice daily has shown a tendency toward a plateau effect, reducing the risk of developing severe bradycardia <40 beats/min (see section "Adverse Reactions").

When used at recommended therapeutic doses, HR is reduced by approximately 10 beats/min both 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 was evaluated in five double-blind, randomized trials (three versus placebo and one each versus atenolol and 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 over 3–4 weeks of treatment demonstrated efficacy based on exercise testing parameters. Efficacy was confirmed with a dose of 7.5 mg twice daily. Specifically, additional benefits of increasing the dose from 5 mg twice daily were demonstrated in a controlled comparative study versus atenolol: total exercise test duration increased by approximately 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, a further increase in exercise duration of nearly 25 seconds was observed. In this study, the antianginal and anti-ischemic properties of ivabradine were confirmed in patients aged ≥65 years. The efficacy of ivabradine at doses of 5 and 7.5 mg twice daily was consistent across all studies based on exercise test parameters (total exercise duration, time to angina-limiting symptoms, time to onset of angina, time to 1 mm ST-segment depression), and was accompanied by a reduction in the frequency of angina attacks by approximately 70%. The twice-daily dosing regimen of ivabradine provided stable and effective action over 24 hours.

In a randomized, placebo-controlled study involving 889 patients, ivabradine administered in addition to atenolol 50 mg once daily demonstrated additional efficacy across all exercise test parameters during the interdose interval (12 hours after oral administration).

Efficacy studies demonstrated that the effectiveness 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 the studies. The antianginal and anti-ischemic efficacy of ivabradine was associated with dose-dependent reduction in HR and significant reduction in rate-pressure product (HR × systolic blood pressure) both at rest and during physical exertion. The effect of ivabradine on blood pressure and peripheral vascular resistance was minimal and not clinically significant.

Sustained reduction in HR was demonstrated in patients treated with ivabradine for at least 1 year (n = 713). No effects on glucose or lipid metabolism were observed.

Antianginal and anti-ischemic efficacy of ivabradine was confirmed in patients with diabetes mellitus (n = 457), with a safety profile similar to that in the general population.

In the large-scale BEAUTIFUL outcome study involving 10,917 patients with ischemic heart disease and left ventricular dysfunction (LVEF < 40%), ivabradine was administered in addition to optimal background therapy (86.9% of patients received β-blockers). The primary composite endpoint was cardiovascular mortality, hospitalization due to acute myocardial infarction (MI), and hospitalization due to onset or worsening of heart failure. The study showed no difference in the primary composite endpoint between the ivabradine and placebo groups (relative risk in the ivabradine group vs. placebo: 1.00; p=0.945).

In a retrospective analysis of the subgroup of patients with symptomatic angina at randomization (n=1507), no safety signals were observed regarding cardiovascular mortality, hospitalization due to acute MI, or heart failure (ivabradine 12.0% vs. placebo 15.5%, p=0.05).

In the large-scale SIGNIFY outcome study involving 19,102 patients with ischemic heart disease without clinical signs of heart failure (LVEF > 40%), ivabradine was administered in addition to optimal background therapy. In this study, a higher dosing regimen than the approved one was used (initial dose: 7.5 mg twice daily [5 mg twice daily for patients aged ≥75 years], with dose titration up to 10 mg twice daily). The primary efficacy endpoint was the composite of cardiovascular mortality or non-fatal MI. The study showed no difference in the incidence of the primary composite endpoint (PCE) between the ivabradine and placebo groups (relative risk ivabradine/placebo 1.08; p=0.197). Bradycardia was observed in 17.9% of patients in the ivabradine group (2.1% in the placebo group). Throughout the study, 7.1% of patients received verapamil, diltiazem, or strong CYP3A4 inhibitors.

A small but statistically significant increase in the incidence of PCE was observed in a pre-specified subgroup of patients with angina class II or higher according to the Canadian Cardiovascular Society (CCS) classification (n=12,049) (annual rate 3.4% vs. 2.9%, relative risk ivabradine/placebo 1.18; p=0.018); however, no such effect was observed in the subgroup of the overall population with CCS class ≥ I angina (n=14,286) (relative risk ivabradine/placebo 1.11; p=0.110).

The use of a higher-than-approved dose in the study partially explains the obtained results.

SHIFT was a multicenter, international, randomized, double-blind, placebo-controlled outcome study involving 6505 adult patients with stable chronic heart failure (CHF) (duration ≥4 weeks), NYHA functional class II–IV, reduced left ventricular ejection fraction (LVEF ≤ 35%), and resting HR ≥70 beats/min.

Patients received standard therapy, including β-blockers (89%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and anti-aldosterone agents (60%). In the ivabradine group, 67% of patients received the drug at a dose of 7.5 mg twice daily. The mean follow-up duration was 22.9 months. Ivabradine treatment was associated with a mean reduction in HR of 15 beats/min compared to the baseline of 80 beats/min. The difference in HR between the 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.

The study demonstrated clinically and statistically significant 18% reduction in the relative risk of the primary composite endpoint (cardiovascular mortality and hospitalization for worsening heart failure) (hazard ratio: 0.82, 95% confidence interval [CI] 0.75–0.90; p<0.0001), evident within the first 3 months of treatment. The absolute risk reduction was 4.2%. The results for the primary endpoint were primarily driven by heart failure-related endpoints: hospitalization for worsening heart failure (absolute risk reduction 4.7%) and heart failure-related mortality (absolute risk reduction 1.1%).

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

	Ivabradine (N=3241) n (%)	Placebo (N=3264) n (%)	Risk ratio [95 % CI]	p-value
Primary composite endpoint	793 (24.47)	937 (28.71)	0.82 [0.75; 0.90]	<0.0001
Components of the composite endpoint: Cardiovascular death Hospitalization due to 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 Hospitalization for any cause Hospitalization due to 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 primary endpoint was observed independently of sex, NYHA class, ischemic or non-ischemic etiology of heart failure, and the presence of diabetes or hypertension in the patient's history.

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

The study demonstrated a significant reduction in the incidence of the primary composite endpoint in the overall patient group receiving β-blocker therapy (hazard ratio: 0.85, 95% CI [0.76; 0.94]). In the subgroup of patients with heart rate ≥ 75 bpm receiving β-blockers at recommended doses, no statistically significant effect was observed on the primary composite endpoint (hazard ratio: 0.97, 95% CI [0.74; 1.28]) or on other secondary endpoints, including hospitalization due to worsening heart failure (hazard ratio: 0.79, 95% CI [0.56; 1.10]) or death due to heart failure (hazard ratio: 0.69, 95% CI [0.31; 1.53]).

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

During a randomized, placebo-controlled study involving 97 patients, data obtained from specialized ophthalmological examinations aimed at assessing cone and rod system function and the visual pathway (electroretinography, static and kinetic visual fields, color perception, visual acuity) in patients treated with ivabradine for chronic stable angina over 3 years did not reveal retinal toxicity.

Pharmacokinetics.

Under physiological conditions, ivabradine is rapidly released and highly water-soluble (> 10 mg/mL). Ivabradine is the S-enantiomer, which showed no in vivo bioconversion. The main active metabolite following medical use 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 is reached approximately within 1 hour. The absolute bioavailability of film-coated tablets is about 40%, due to first-pass metabolism in the gut and liver.

Concomitant food intake delays absorption by approximately 1 hour and increases plasma concentration by 20–30%. To reduce intra-individual variability in drug concentration, it is recommended to take tablets with food (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 dose of 5 mg twice daily, the maximum plasma concentration is 22 ng/mL (coefficient of variation [CV] = 29%). The average 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) oxidation system. The main active metabolite is the N-desmethyl derivative (S 18982), with a concentration reaching 40% of the parent compound. CYP3A4 is also involved in the metabolism of this active metabolite. Ivabradine has low affinity for CYP3A4, does not activate it, and does not clinically significantly inhibit it; therefore, it is unlikely to alter the metabolism or plasma concentration of CYP3A4 substrates. However, strong inhibitors and inducers of CYP3A4 may 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 is 400 mL/min, and renal clearance is 70 mL/min. Metabolite excretion occurs equally via urine and feces. Approximately 4% of the oral dose is excreted unchanged in urine.

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

Special patient groups.

Elderly patients: Pharmacokinetic parameters (AUC and Cmax) in elderly (≥ 65 years) and very elderly (≥ 75 years) patients 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 the pharmacokinetics of ivabradine is minimal due to the small contribution of renal clearance (about 20%) to the total elimination of ivabradine and its main metabolite S 18982 (see section "Dosage and administration").

Hepatic impairment: In patients with mild hepatic impairment (Child-Pugh score ≤ 7), AUC of ivabradine and its main active metabolite was approximately 20% higher than in patients with normal liver function. Available data are insufficient to draw conclusions regarding use in patients with moderate hepatic impairment. 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 an almost linear relationship between heart rate reduction and increasing plasma concentrations of ivabradine and S 18982 at doses of 15–20 mg twice daily. At higher doses, heart rate reduction becomes disproportionate to plasma concentration and tends to reach a plateau. High plasma concentrations of ivabradine may result from co-administration with strong CYP3A4 inhibitors, potentially leading to excessive heart rate reduction; 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.

Raiemon 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 adult patients who have contraindications or limitations to the use of

β-blockers;

• or in combination with β-blockers to patients whose condition is inadequately controlled on optimal β-blocker dosage.

Treatment of chronic heart failure.

Raiemon is indicated for patients with chronic heart failure of NYHA functional classes II–IV with systolic dysfunction, sinus rhythm, and heart rate ≥ 75 bpm, in combination with standard therapy, including β-blockers, or in cases of contraindications or intolerance to β-blockers (see section "Pharmacodynamics").

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients;
• resting heart rate < 70 bpm prior to initiation of treatment;
• cardiogenic shock;
• acute myocardial infarction;
• severe arterial hypotension (< 90/50 mm Hg);
• severe hepatic impairment;
• sick sinus syndrome;
• sinoatrial block;
• unstable or acute heart failure;
• dependence on a pacemaker (heart rate controlled exclusively by a 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 "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 or breastfeeding, or reproductive age in women not using adequate 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 prolonging the QT interval:

• cardiovascular agents (e.g., quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone);
• non-cardiovascular agents (e.g., 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 potentiate QT prolongation. If such combination is necessary, careful cardiac monitoring should be ensured (see section "Special precautions for use").

Combinations requiring caution.

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, especially in patients with congenital or drug-induced long QT syndrome.

Pharmacokinetic interactions.

Cytochrome P450 3A4 (CYP3A4)

Ivabradine is metabolized exclusively by CYP3A4 and is a very weak inhibitor of this enzyme. Ivabradine has been shown not to affect the metabolism or plasma concentrations of other CYP3A4 substrates (weak, moderate, or strong inhibitors). However, CYP3A4 inhibitors and inducers 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, whereas inducers decrease them. Increased plasma concentrations of ivabradine may 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"). Strong CYP3A4 inhibitors such as ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increase the average plasma concentration of ivabradine by 7–8 times.

Moderate CYP3A4 inhibitors: specific interaction 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 concentration (2–3 times in AUC) and additional reduction in heart rate by 5 bpm. Concomitant use of ivabradine with these drugs is contraindicated (see section "Contraindications").

Not recommended combinations.

Grapefruit juice: concomitant intake of grapefruit juice and ivabradine doubles the plasma concentration of the drug. Therefore, consumption of grapefruit juice should be avoided.

Combinations requiring precautions.

Moderate CYP3A4 inhibitors: concomitant use of ivabradine with other moderate inhibitors (e.g., fluconazole) may be initiated at a dose of 2.5 mg twice daily if resting heart rate exceeds 70 bpm; heart rate should be monitored.

CYP3A4 inducers: CYP3A4 inducers (e.g., rifampicin, barbiturates, phenytoin, St John’s wort (Hypericum perforatum)) may reduce the concentration and efficacy of ivabradine. Concomitant use of CYP3A4-inducing drugs may necessitate dose adjustment of ivabradine. When ivabradine 10 mg twice daily is coadministered with St John’s wort, the AUC of ivabradine is reduced by half. Therefore, 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. Furthermore, ivabradine has no clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, or on the pharmacokinetics and pharmacodynamics of digoxin and warfarin, as well as on the pharmacodynamics of acetylsalicylic acid.

In Phase III clinical trials, ivabradine was routinely used concomitantly with angiotensin-converting enzyme inhibitors, angiotensin II antagonists, β-blockers, diuretics, anti-aldosterone agents, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetic agents, acetylsalicylic acid, and other antithrombotic agents, without any safety concerns.

Special precautions for use.

Special warnings.

Insufficient beneficial effect on clinical outcomes in patients with symptomatic chronic stable angina. Ranexa 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 (e.g., myocardial infarction or cardiovascular death) (see section «Pharmacodynamics»).

Heart rate measurement. Given the potential for significant fluctuations in heart rate (HR), serial HR measurements, ECG, or continuous ambulatory monitoring should be performed when assessing resting HR before initiating treatment with Ranexa and when dose titration is required in patients taking ivabradine. This also applies to patients with low HR, especially if HR decreases to less than 50 bpm, or after dose reduction (see section «Dosage and administration»).

Arrhythmias. Ranexa is not intended for the treatment or prevention of arrhythmias and may lose efficacy if tachyarrhythmia (ventricular or supraventricular) develops in the patient. Therefore, Ranexa is not recommended for use in patients with atrial fibrillation and other types of arrhythmias affecting sinus node function.

Patients receiving Ranexa have an increased risk of developing atrial fibrillation (see section «Adverse reactions»). Atrial fibrillation occurs more frequently in patients who are concurrently taking amiodarone or potent class I antiarrhythmic drugs. Regular clinical monitoring for atrial fibrillation (persistent or paroxysmal) is recommended during treatment with Ranexa, including ECG monitoring when clinically justified (e.g., worsening angina symptoms, palpitations, irregular pulse).

Patients should be informed about the signs and symptoms of atrial fibrillation and advised to promptly report them to their physician.

If atrial fibrillation develops during treatment, the continued use of Ranexa should be carefully reconsidered based on benefit-risk assessment.

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

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

Patients with low heart rate. Ranexa should not be prescribed to patients whose resting HR before treatment initiation is < 70 bpm (see section «Contraindications»).

If during therapy a sustained decrease in resting HR to < 50 bpm occurs, or if the patient develops symptoms of bradycardia (dizziness, weakness, hypotension), the dose should be gradually reduced or treatment discontinued if HR remains below 50 bpm or bradycardia symptoms persist (see section «Dosage and administration»).

Combination with calcium channel blockers. Concomitant use of Ranexa 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 the use of Ranexa in combination with nitrates or dihydropyridine calcium channel blockers (e.g., amlodipine). Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established (see section «Pharmacodynamics»).

Chronic heart failure. Treatment is possible only if heart failure is stable. Ranexa should be used with caution in patients with NYHA class IV heart failure due to limited data in this population.

Stroke. Ranexa is not recommended for immediate use following a stroke, as there are no data on the use of the drug in this situation.

Visual function. Ivabradine affects retinal function. There is no evidence of toxic effects of long-term ivabradine treatment on the retina (see section «Pharmacodynamics»). If any unexpected visual disturbances occur, treatment should be discontinued. The drug should be prescribed with caution to patients with retinitis pigmentosa.

Precautions for use.

Patients with arterial hypotension. Due to insufficient data, Ranexa should be used with caution in patients with mild to moderate arterial hypotension. Ranexa is contraindicated in patients with severe arterial hypotension (blood pressure < 90/50 mm Hg) (see section «Contraindications»).

Atrial fibrillation – Cardiac arrhythmias. There is no evidence of risk of (excessive) bradycardia upon restoration of sinus rhythm during pharmacological cardioversion in patients treated with ivabradine. However, due to insufficient data, non-emergency DC cardioversion should not be performed earlier than 24 hours after the last dose of Ranexa.

Patients with congenital long QT syndrome or receiving QT-prolonging drugs. The use of Ranexa should be avoided in patients with congenital long QT syndrome or those receiving QT-prolonging drugs (see section «Interaction with other medicinal products and other forms of interaction»). If such combination therapy is necessary, careful cardiac monitoring is recommended.

Heart rate reduction due to ivabradine may exacerbate QT interval prolongation and may lead to severe arrhythmias, including torsades de pointes.

Patients with arterial hypertension requiring changes in therapy. When modifying treatment in patients with chronic heart failure receiving ivabradine, blood pressure should be monitored at regular intervals (see section «Adverse reactions»).

Excipients

This medicinal product contains lactose.

Therefore, the drug should not be used in patients with rare hereditary conditions such as galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption syndrome.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., essentially sodium-free.

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 the drug on reproductive function. Embryotoxic and teratogenic effects have also been observed. The potential risk in humans is unknown; therefore, the use of Ranexa during pregnancy is contraindicated (see section «Contraindications»).

Breastfeeding. Animal studies indicate that ivabradine passes into breast milk. Therefore, the use of Ranexa during breastfeeding is contraindicated (see section «Contraindications»). Women requiring treatment with ivabradine should discontinue breastfeeding and choose an alternative method of infant feeding.

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

Ability to influence reaction speed when driving or operating machinery.

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

A dedicated study in healthy volunteers demonstrated that ivabradine does not affect the ability to drive. 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 in the form of phosphenes (see section «Adverse reactions»). The possibility of such visual phenomena should be considered when driving or operating machinery, particularly in situations where light intensity may change suddenly, especially during night driving.

Method of Administration and Dosage.

Depending on the required dose, film-coated tablets containing 5 mg or 7.5 mg of ivabradine should be prescribed.

Raiemon should be prescribed to adult patients only.

Raiemon 5 mg film-coated tablets may be divided into equal doses.

Raiemon 7.5 mg film-coated tablets 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 repeated heart rate measurements, ECG, or 24-hour ambulatory monitoring.

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

If there is no symptom improvement in angina pectoris within 3 months after starting treatment, Raiemon should be discontinued.

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

If during treatment the heart rate decreases to < 50 bpm at rest or the patient experiences symptoms 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 (half of a 5 mg tablet twice daily). Heart rate should be monitored after dose reduction (see section "Special Warnings and Precautions for Use"). Treatment should be discontinued if the heart rate remains < 50 bpm or if bradycardia symptoms persist despite dose reduction.

Treatment of chronic heart failure.

Treatment should only be initiated in patients with stable heart failure. It is recommended that the drug be prescribed by a physician experienced in managing chronic heart failure.

The recommended initial dose of Raiemon is 5 mg twice daily. After two weeks of treatment, the dose may be increased to 7.5 mg twice daily if the resting heart rate remains > 60 bpm, or reduced to 2.5 mg twice daily (half of a 5 mg tablet twice daily) if the resting heart rate remains < 50 bpm or if the patient experiences symptoms related to bradycardia (dizziness, weakness, hypotension). If the heart rate is between 50–60 bpm, the dose of 5 mg twice daily should be maintained.

If during treatment a sustained decrease in resting heart rate to < 50 bpm or symptoms of bradycardia occur while receiving ivabradine 7.5 or 5 mg twice daily, the dose should be 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.

Treatment should be discontinued if the heart rate remains < 50 bpm or bradycardia symptoms persist during treatment (see section "Special Warnings and Precautions for Use").

Special patient populations.

Elderly patients. For patients aged 75 years and older, treatment should be initiated at a lower starting dose (2.5 mg twice daily, i.e., half of a 5 mg tablet twice daily). The dose may be gradually increased if necessary.

Renal impairment. Patients with renal insufficiency and creatinine clearance > 15 ml/min do not require dose adjustment (see section "Pharmacokinetics").

There are no data on the use of the drug in patients with creatinine clearance < 15 ml/min. Ivabradine should be used with caution in such patients.

Hepatic impairment. Patients with mild hepatic impairment do not require dose adjustment. Raiemon should be prescribed with caution in patients with moderate hepatic impairment. Raiemon 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 systemic drug concentration (see sections "Contraindications" and "Pharmacokinetics").

Method of administration.

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

Children.

Safety and efficacy of ivabradine in children (< 18 years of age) have not been established. No data are available.

Overdose.

Overdose may lead to severe and prolonged bradycardia (see section "Adverse Reactions"). Severe bradycardia requires symptomatic treatment in specialized medical facilities. In cases of bradycardia with poor hemodynamic tolerance, intravenous β-stimulating agents such as isoprenaline may be considered. Temporary use of a cardiac pacemaker may be considered if necessary.

Adverse reactions

The most common adverse reactions of ivabradine are visual disturbances (phosphenes) (14.5%) and bradycardia (3.3%), which are dose-dependent and related to the pharmacological action of the drug.

During clinical studies, the following adverse reactions were observed, listed according to frequency categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); frequency not known (cannot be estimated from the available data).

System organ class	Frequency of occurrence	Predominant term
Blood and lymphatic system disorders	Uncommon	Eosinophilia
Metabolism and nutrition disorders	Uncommon	Hyperuricemia
Nervous system disorders	Common	Headache, usually during the first month of treatment
		Dizziness, possibly related to bradycardia
	Uncommon*	Fainting, possibly related to bradycardia
Eye disorders	Very common	Visual disturbances (phosphenes)
	Common	Blurred vision
	Uncommon*	Diplopia
		Worsening of vision
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, QT interval prolongation on ECG
	Rare	Second- and third-degree AV block
		Sinus node dysfunction syndrome
Vascular disorders	Common	Uncontrolled blood pressure
	Uncommon*	Hypotension, possibly 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
	Isolated*	Erythema
		Itching
		Urticaria
Musculoskeletal and connective tissue disorders	Uncommon	Muscle spasms
Renal and urinary disorders	Uncommon	Increased blood creatinine levels
General disorders and administration site conditions	Uncommon*	Asthenia, possibly related to bradycardia
		Fatigue, possibly related to bradycardia
	Isolated*	Malaise, possibly related to bradycardia

* Frequency based on clinical trials for adverse events identified in spontaneous reports.

Description of some adverse reactions.

Visual phenomena (phosphenes) were observed in 14.5% of patients as a temporary increase in brightness in a limited area of the visual field. They usually occur in response to a sudden change in light intensity. Phosphenes have also been described as halos, image decomposition (stroboscopic or 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%) disappearing during therapy. Less than 1% of patients modified their daily activities or discontinued 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 study, 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 all double-blind, controlled phase II/III clinical trials lasting at least 3 months and involving over 40,000 patients demonstrated that the incidence of atrial fibrillation was 4.86% in patients treated with ivabradine compared to 4.08% in the control group, corresponding to a risk ratio of 1.26 with a 95% confidence interval [1.15–1.39].

In the SHIFT study, more episodes of increased blood pressure were observed in patients receiving ivabradine (7.1%) compared to those receiving 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.

If any adverse reaction listed in this instruction worsens, or if any other reaction not listed in this instruction occurs, consult a physician.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

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

Packaging.

14 film-coated tablets in a blister.

2 or 4 blisters in a cardboard box together with the instructions for medical use.

Prescription category.

Prescription only.

Manufacturer.

Gedeon Richter Romania S.A.

Manufacturer's address and location of its operations.

99–105 Calea Cucului Street, Târgu-Mureș, Mureș County, 540306, Romania.