Ivab-7.5®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IVAB-7.5® (IVAB-7.5)

Composition:

Active substance: ivabradine;

One film-coated tablet contains ivabradine hydrochloride equivalent to 7.5 mg of ivabradine;

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

Coating: hypromellose, titanium dioxide (E 171), macrogol 6000, glycerol, iron oxide red (E 172), magnesium stearatе.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: pinkish-brown, elongated, biconvex film-coated tablets with a break line on three sides and smooth on one side.

Pharmacotherapeutic group. Cardiac drugs. ATC code C01EB17.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ivabradine is a cardiovascular agent that initiates a new pharmacotherapeutic class. Ivabradine acts exclusively on heart rate. It works by selectively and specifically inhibiting the f-channels of the cardiac sinus node, thereby controlling the spontaneous diastolic depolarization of the sinus node and consequently reducing heart rate. In the heart, 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 h-channels in the retina, which are structurally similar to the f-channels of the cardiac sinus node. This 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 h-channels by ivabradine leads to the occurrence of phosphenes, which may unexpectedly appear in patients. Phosphenes are transient enhanced brightness in a limited area of the visual field.

The main pharmacodynamic property of ivabradine is selective, dose-dependent reduction of heart rate (HR). Analysis of HR reduction with ivabradine administered at doses up to 20 mg twice daily showed a tendency toward a plateau effect, which reduces the risk of developing severe bradycardia < 40 beats/min. When used at recommended therapeutic doses (5–7.5 mg twice daily), HR decreases by approximately 0.10 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:

• according to electrophysiological studies, ivabradine did not affect atrioventricular or intraventricular conduction or corrected QT interval;
• in patients with left ventricular dysfunction (left ventricular ejection fraction 30–45%), ivabradine had no negative effect on ejection fraction parameters.

Ivabradine at a dose of 5 mg twice daily demonstrated efficacy in exercise testing parameters already after 3–4 weeks of treatment. Furthermore, additional benefits were observed with increased ivabradine dose up to 7.5 mg twice daily compared to atenolol: exercise test duration increased by 1 minute after one month of treatment with ivabradine 5 mg twice daily; after 3 months of increasing the ivabradine dose to 7.5 mg twice daily, further prolongation of exercise duration by almost 25 seconds was observed. Antianginal and anti-ischemic properties of ivabradine have also been confirmed in patients aged 65 years and older. The efficacy of ivabradine at doses of 5–7.5 mg twice daily is consistent in exercise testing parameters (total exercise duration, time to onset of angina-limiting symptoms, time to angina attack, time to development of 1 mm ST-segment depression) and was accompanied by a reduction in the number of angina attacks by approximately 70%. The twice-daily dosing regimen of ivabradine provides stable effective action over 24 hours.

When used as an add-on to 50 mg atenolol once daily, ivabradine demonstrates additional efficacy across all exercise test parameters at the interdose interval (12 hours after tablet intake).

Ivabradine maintains full efficacy throughout the entire 3–4 month treatment period. No signs of pharmacological tolerance (loss of efficacy) or rebound effect after abrupt discontinuation of the drug have been observed. Antianginal and anti-ischemic efficacy of ivabradine are related to dose-dependent HR reduction and significant reduction in the rate-pressure product (RPP) at rest and during physical exercise (RPP – a parameter reflecting myocardial oxygen demand, RPP = HR × systolic blood pressure). The effect of ivabradine on blood pressure and peripheral vascular resistance is minimal and clinically insignificant.

Ivabradine does not affect glucose and lipid metabolism during long-term use (up to 1 year).

In patients with diabetes mellitus, anti-ischemic and antianginal efficacy and safety of ivabradine have been confirmed.

Specific ophthalmological investigations of rod and cone system function, as well as ascending visual pathways using electroretinography, analysis of static and kinetic visual fields, color vision, and visual acuity in patients treated with ivabradine for chronic stable angina over 3 years, demonstrated absence of retinal toxicity.

Pediatric use

When ivabradine was administered to children aged 6 to 12 months starting at 0.02 mg/kg twice daily, to children aged 1 to 3 years and aged 3 to 18 years with body weight < 40 kg starting at 0.05 mg/kg twice daily, and to children aged 3 to 18 years with body weight ≥ 40 kg starting at 2.5 mg twice daily, subsequent doses were adjusted according to therapeutic response up to maximum doses of 0.2 mg/kg twice daily, 0.3 mg/kg twice daily, and 15 mg twice daily, respectively. The medicinal product was administered in liquid oral form or as tablets, with no pharmacokinetic difference between the two forms proven in a study conducted in healthy adult volunteers. A 20% reduction in heart rate without bradycardia during the titration period between weeks 2 and 8 was achieved in 69.9% of patients. Mean doses providing a 20% reduction in HR were 0.13±0.04 mg/kg twice daily, 0.10±0.04 mg/kg twice daily, and 4.1±2.2 mg twice daily, respectively, in age groups 1–3 years, 3–18 years with body weight < 40 kg, and 3–18 years with body weight ≥ 40 kg. An increase in left ventricular ejection fraction (from 31.8% to 45.3%) and improvement according to the New York Heart Association classification were also observed in 37.7% of patients. However, these improvements were statistically non-significant. The safety profile in children is similar to that in adults with chronic heart failure.

Long-term effects of ivabradine on growth, pubertal and general development, as well as long-term efficacy in reducing cardiovascular morbidity and mortality in children, have not been studied.

The European Medicines Agency has waived the obligation to submit results of studies on the use of ivabradine for the treatment of angina in pediatric patients across all subgroups.

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

Pharmacokinetics.

Under physiological conditions, ivabradine is rapidly released from tablets and readily dissolves in water (> 10 mg/mL). Ivabradine is the S-enantiomer, which does not exhibit in vivo bioconversion. The main active metabolite of ivabradine in the human body is its N-desmethylated 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. Absolute bioavailability of ivabradine is nearly 40% due to first-pass effect through the gastrointestinal tract and liver.

Concomitant food intake delays absorption by approximately 1 hour and increases plasma concentration by 20–30%. To avoid intra-individual fluctuations in plasma concentration of ivabradine, the drug is recommended to be taken with meals.

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

Biotransformation. Ivabradine is extensively metabolized in the liver and intestine via oxidation exclusively by the cytochrome P450 3A4 (CYP3A4) system. The main active metabolite of ivabradine is its N-desmethylated derivative (S 18982), with exposure approximately 40% of that of ivabradine hydrochloride. The main active metabolite is also metabolized by the CYP3A4 enzyme system.

Ivabradine has low chemical affinity for CYP3A4 and does not clinically significantly induce or inhibit it; therefore, it does not significantly alter the metabolism or plasma concentration of CYP3A4 substrates. In contrast, potent inhibitors and inducers of CYP3A4 may substantially affect plasma concentrations of ivabradine.

Elimination. The elimination half-life of ivabradine and its main metabolite from plasma is 2 hours (70–75% of the area under the pharmacokinetic curve) and 11 hours, respectively. Total clearance is approximately 400 mL/min, renal clearance approximately 70 mL/min. Metabolites are excreted in feces and urine at similar rates. Approximately 4% of the active substance is excreted unchanged in urine.

Linearity/non-linearity. The kinetics of ivabradine are linear within the range of oral doses from 0.5 to 24 mg.

Special patient groups

Advanced age. No pharmacokinetic differences (AUC and Cmax) were observed between elderly patients (≥ 65 years) or very elderly patients (≥ 75 years) and 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 proportion of renal clearance (approximately 20%) of total clearance of ivabradine and its main metabolite S 18982.

Hepatic impairment: in patients with mild hepatic impairment (Child–Pugh score below 7 points), the AUC of unbound ivabradine and its main metabolite is approximately 20% higher than in patients with normal liver function. Data are insufficient to draw definitive conclusions in patients with moderate hepatic impairment. Data on use in patients with severe hepatic impairment are lacking.

Children: the pharmacokinetic profile of ivabradine when administered according to a dosing regimen titrated according to age and body weight in children aged 6 months to 18 years with chronic heart failure is similar to that in adult patients.

Pharmacokinetic/pharmacodynamic (PK/PD) relationship.

Analysis of the PK/PD relationship showed a linear dependence of HR reduction on increasing plasma concentrations of ivabradine and S 18982 at doses from 15 to 20 mg twice daily. At higher doses, the reduction in heart rate loses proportional dependence on plasma concentrations of ivabradine and tends toward a plateau effect. High exposure to ivabradine when co-administered with potent CYP3A4 inhibitors may lead to excessive reduction in heart rate, although the risk is reduced with moderate CYP3A4 inhibitors.

The relationship between pharmacokinetics and pharmacodynamics of ivabradine in children aged 6 months to 18 years is analogous to the PK/PD relationship in adults.

Clinical Characteristics.

Indications.

Symptomatic treatment of chronic stable angina.

IVABRADINE-7.5® 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-adrenoblockers;
• in combination with β-adrenoblockers to patients whose condition is insufficiently controlled with optimal doses of β-adrenoblockers.

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 any of the excipients.
• Resting heart rate < 70 beats/min before initiation of treatment.
• Cardiogenic shock.
• Acute myocardial infarction.
• Severe arterial hypotension (blood pressure < 90/50 mm Hg).
• Severe hepatic impairment.
• Sinoatrial node dysfunction syndrome.
• Sinoatrial block.
• Unstable or acute heart failure.
• Presence of a cardiac pacemaker in the patient (heart rate controlled exclusively by a pacemaker).
• Unstable angina.
• Third-degree atrioventricular block.
• Combination with strong CYP3A4 inhibitors: antifungal agents – azole derivatives (ketoconazole and itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir), and nefazodone.
• 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 types of interactions").
• Pregnancy, breastfeeding, and reproductive age in women not using appropriate contraceptive measures (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions.

Pharmacodynamic interactions.

Not recommended combinations

Drugs that prolong the QT interval

• Cardiovascular: quinidine, disopyramide, bepridil, sotalol, amiodarone, ibutilide.
• 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 combination therapy is necessary, careful monitoring of cardiac function should be performed throughout treatment.

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, especially in patients with long QT syndrome, either 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. Studies have shown that ivabradine does not affect the metabolism and plasma concentrations of other CYP3A4 substrates (weak, moderate, and strong inhibitors). 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 reduce them. Increased plasma concentrations of ivabradine may increase the risk of excessive bradycardia.

Contraindicated combinations.

Concomitant use of ivabradine and 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. 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: co-administration of ivabradine with agents that reduce heart rate, such as diltiazem or verapamil, leads to increased exposure to ivabradine (2–3 times higher AUC) and additional reduction in heart rate by 5 beats/min. Concomitant use of ivabradine with these drugs is contraindicated.

Not recommended combinations

Grapefruit juice. Concomitant intake of grapefruit juice increases exposure to ivabradine by two-fold. Therefore, consumption of grapefruit juice should be limited during ivabradine treatment.

Combinations requiring caution during use.

Moderate CYP3A4 inhibitors (e.g., fluconazole): combined use of ivabradine with other moderate CYP3A4 inhibitors may be considered if the initial dose is 2.5 mg twice daily and heart rate is not below 70 beats/min. Heart rate monitoring is required.

Inducers of CYP3A4 such as rifampicin, barbiturates, phenytoin, and St. John’s wort (Hypericum perforatum). Concomitant use of these drugs with ivabradine may lead to reduced concentration and efficacy of ivabradine, and dose adjustment of ivabradine may be necessary. When ivabradine 10 mg twice daily was administered concomitantly with St. John’s wort, ivabradine concentration was reduced by half. Use of St. John’s wort should be avoided during ivabradine treatment.

Other combinations. The following drugs do not have a clinically significant effect on the pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), calcium channel blockers of the dihydropyridine class (amlodipine, lacidipine), digoxin, and warfarin. Furthermore, ivabradine did not have a clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, and lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin and warfarin, or on the pharmacodynamics of aspirin. Combination therapy with ivabradine in the usual therapeutic regimen is safe with the following drugs: angiotensin-converting enzyme inhibitors, angiotensin II antagonists, diuretics, anti-mineralocorticoid agents, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetic agents, aspirin, and other antiplatelet 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 potential for significant fluctuations in heart rate, serial measurements of resting heart rate, ECG, or 24-hour ambulatory monitoring should be performed before initiating treatment and when dose titration is required in patients receiving ivabradine. This also applies to patients with low baseline heart rate, especially if heart rate decreases below 50 bpm, or after dose reduction (see section "Dosage and administration").

Arrhythmias. Ivabradine should not be used for prevention or treatment of arrhythmias. If a tachyarrhythmia (ventricular or supraventricular) develops during therapy, continued use 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.

Patients receiving ivabradine have an increased risk of developing atrial fibrillation (see section "Adverse reactions"). Atrial fibrillation occurs more frequently in patients who are also taking amiodarone or potent class I antiarrhythmic drugs. During treatment with ivabradine, regular clinical monitoring is recommended to allow timely diagnosis of atrial fibrillation (paroxysmal or persistent), 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 report them to their physician. If atrial fibrillation develops during treatment, the benefit-risk ratio of continuing ivabradine therapy should be carefully evaluated.

Patients with chronic heart failure (CHF), intraventricular conduction disorders (left bundle branch block, right bundle branch block), or ventricular dyssynchrony should be closely monitored.

Ivabradine is not recommended in patients with second-degree atrioventricular block.

Patients with bradycardia. Ivabradine should not be prescribed to patients whose resting heart rate before treatment initiation is < 70 bpm (see section "Contraindications").

If heart rate at rest decreases below 50 bpm during treatment, or if the patient experiences symptoms of bradycardia (dizziness, weakness, hypotension), the dose should be gradually reduced. Treatment should be discontinued if heart rate remains below 50 bpm or if bradycardia symptoms persist.

Chronic heart failure. When deciding to initiate ivabradine therapy in heart failure, the patient's condition must be assessed. Treatment is only appropriate 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. The toxic effect of long-term ivabradine use on the retina has not been established (see section "Pharmacodynamics"). If any unexpected visual disturbances occur, treatment should be discontinued. Ivabradine should be prescribed with caution in patients with retinitis pigmentosa.

Use with calcium channel blockers. Concomitant use of ivabradine with calcium channel blockers that reduce heart rate, such as verapamil or diltiazem, is not recommended. The safety of using ivabradine concurrently with nitrates and dihydropyridine calcium channel blockers such as amlodipine has not been established. The potential for enhanced efficacy of ivabradine when used in combination with dihydropyridine calcium channel blockers has not been confirmed.

Precautionary measures.

Patients with arterial hypotension. Data on the use of ivabradine in patients with mild to moderate hypotension are limited. Therefore, the drug should be used with caution in such patients. Ivabradine is contraindicated in patients with severe hypotension (blood pressure < 90/50 mm Hg).

Atrial fibrillation. Cardiac arrhythmias. The risk of (excessive) bradycardia upon restoration of normal sinus rhythm during pharmacological cardioversion while taking ivabradine has not been established. However, in the absence of sufficient data, elective direct-current cardioversion should not be performed earlier than 24 hours after the last dose of ivabradine.

Patients with congenital long QT interval or those taking drugs that prolong the QT interval should avoid using ivabradine. If ivabradine must be prescribed to such patients, careful cardiological monitoring is required. Reduction in heart rate due to ivabradine may exacerbate QT interval prolongation, which is associated with the development of severe arrhythmias, particularly torsades de pointes.

Patients with arterial hypertension requiring changes in therapy. In clinical trials, more episodes of increased blood pressure (7.1%) were observed in patients receiving 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 efficacy of ivabradine. When changes in therapy are introduced in patients with CHF receiving ivabradine, blood pressure 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.

Use during pregnancy or breastfeeding.

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

Pregnancy. Data on the use of ivabradine in pregnant women are insufficient or lacking. Animal studies have shown reproductive toxicity, with embryotoxic and teratogenic effects observed. The potential risk to humans is not established. Therefore, ivabradine is contraindicated during pregnancy.

Breastfeeding. Animal studies have shown that ivabradine is excreted in breast milk. Therefore, the drug is contraindicated in breastfeeding women. 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 been shown not to impair the ability to drive or operate machinery. However, in 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 luminous phenomena (phosphenes), typically triggered by sudden changes in light intensity. This should be taken into account when driving, especially at night, or operating machinery.

Method of Administration and Dosage.

For oral use.

To be prescribed to adult patients.

Take twice daily: in the morning and in the evening with meals.

The tablet of the drug IVAB-7.5® must not be divided.

Symptomatic treatment of chronic stable angina.

Decisions regarding initiation of treatment or dose titration should 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 HR remains > 60 beats per minute (bpm). The maintenance dose should not exceed 7.5 mg twice daily.

If no improvement in angina symptoms is observed 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 HR during 3 months of treatment.

If during treatment resting HR decreases to < 50 bpm or the patient experiences symptoms indicative 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. HR should be monitored after dose reduction (see section "Special Warnings and Precautions for Use"). The drug should be discontinued if HR 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 chronic heart failure (CHF) by physicians experienced in the management of CHF.

The recommended initial dose of ivabradine is 5 mg* twice daily. After two weeks of treatment, the dose may be increased to 7.5 mg twice daily if resting HR remains > 60 bpm during treatment; or the dose should be reduced to 2.5 mg* twice daily if resting HR remains < 50 bpm or if the patient experiences symptoms related to bradycardia (dizziness, weakness, arterial hypotension). If resting HR is within the range of 50–60 bpm, the dose of ivabradine 5 mg* twice daily should be maintained unchanged.

If during treatment resting HR decreases to < 50 bpm or the patient experiences symptoms related to bradycardia while receiving ivabradine 7.5 mg or 5 mg* twice daily, the dose should be gradually reduced to the next lower level. If resting HR 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 should be discontinued if resting HR remains < 50 bpm or if bradycardia symptoms persist (see section "Special Warnings and Precautions for Use").

Special patient categories.

Elderly patients. In patients aged 75 years and older, treatment should be initiated at a lower starting dose (2.5 mg* twice daily). If further reduction of HR is required, the dose may be gradually increased.

Patients with renal impairment. Dose adjustment is not required in patients with creatinine clearance > 15 ml/min. Due to insufficient data, ivabradine should be used with caution in patients with creatinine clearance < 15 ml/min.

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

* - use ivabradine preparation of corresponding dosage strength.

Children.

The safety and efficacy of ivabradine in children under 18 years of age for the treatment of chronic heart failure have not been established.

Available data are described in the sections "Pharmacokinetics" and "Pharmacodynamics," but they are insufficient to establish recommendations for drug use.

Overdose.

Overdose may cause severe and prolonged bradycardia.

Severe bradycardia requires symptomatic treatment in specialized medical facilities. In cases of bradycardia with hemodynamic compromise, intravenous beta-stimulating agents such as isoprenaline are recommended. In extremely severe cases, temporary cardiac pacing may be considered.

Adverse reactions.

The most common adverse effects of ivabradine are visual phenomena (phosphenes) and bradycardia, which are dose-dependent and related to its pharmacological mechanism of action. The adverse reactions listed below may occur during treatment with the drug, classified 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).

* Frequency of adverse reactions based on data from spontaneous reports.

Description of some adverse reactions.

Visual phenomena (phosphenes) were observed in 14.5% of patients as temporary increases in brightness within a limited area of the visual field. Their occurrence is usually triggered by 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). The first episodes of phosphenes typically occur within the first 2 months of treatment and may recur later. Overall, phosphenes were generally reported as mild to moderate in severity. All cases of phosphenes resolved during or after discontinuation of treatment, with the majority (77.5%) resolving during therapy. Less than 1% of patients required changes in 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. In 0.5% of patients, severe bradycardia occurred, with heart rate at or below 40 beats per minute.

In a study, atrial fibrillation was observed in 5.3% of patients receiving ivabradine, compared to 3.8% in the placebo group. A pooled analysis of all double-blind, placebo-controlled Phase II and 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 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 drug registration is important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are obliged to report any suspected adverse effects through the national reporting system.

Shelf life. 2 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 ºC, in a place inaccessible to children.

Packaging

14 tablets in a blister pack, 2 blisters per cardboard package.

Prescription category. Prescription only.

Manufacturer. Bafna Pharmaceuticals Ltd., India.

Manufacturer's address and location.

147, Madhavaram Red Hills Road, Grantlyon Village, Vadakarai, Chennai, Tamil Nadu IN 600052, India.

Marketing Authorization Holder. SCAN BIOTECH LTD, India.

Address of the Marketing Authorization Holder.

E-4/300, Arera Colony Extension, 462016, Bhopal, (M.P.) India.