Ivab-5®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IVAB-5® (IVAB-5)

Composition:

Active substance: ivabradine;

One film-coated tablet contains ivabradine hydrochloride equivalent to 5 mg of ivabradine;

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

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

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics: brownish-pink, elongated, biconvex film-coated tablets with a break line on three sides and smooth on one side.

Pharmacotherapeutic group. Other cardiac preparations. ATC code C01EB17.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Ivabradine is a substance that exclusively reduces heart rate through selective and specific inhibition of the I_f channels of the cardiac pacemaker, which helps control spontaneous diastolic depolarization in the sinus node and regulate heart rate. The drug exerts a specific cardiological effect on the sinus node without affecting intra-atrial, atrioventricular, or intraventricular conduction time, myocardial contractility, or ventricular repolarization.

Ivabradine may also interact with Ih channels in the retina, which are similar to cardiac I_f channels. The drug participates in the temporal resolution capacity of the visual system, shortening the retinal response to bright light stimulation. Under triggering factors (e.g., sudden change in light intensity), partial inhibition of Ih channels by ivabradine enhances light responses, which patients may occasionally perceive. Such light phenomena (phosphenes) are described as transient increases in brightness within a limited area of the visual field (see section "Adverse reactions").

Pharmacodynamic effects

The primary pharmacodynamic effect of ivabradine in humans is a specific, dose-dependent reduction in heart rate. Analysis of heart rate reduction with doses up to 20 mg twice daily has shown a tendency toward a plateau effect, indicating a low risk of developing severe bradycardia with a heart rate below 40 beats per minute (see section "Adverse reactions").

At recommended doses, heart rate decreases by approximately 10 beats per minute at rest and during physical exertion. This leads to reduced cardiac workload and decreased myocardial oxygen consumption. Ivabradine does not affect intrinsic cardiac conduction, contractility (no negative inotropic effect), or ventricular repolarization:

• ivabradine does not affect atrioventricular conduction or intraventricular conduction time, or the corrected QT interval;
• ivabradine has no negative effect on ejection fraction in patients with left ventricular dysfunction (left ventricular ejection fraction from 30% to 45%).

Clinical efficacy and safety

Exercise testing confirms the efficacy of ivabradine at doses of 5 mg twice daily after 3–4 weeks of treatment. The dose of 7.5 mg twice daily is also effective. Compared to atenolol, an additional beneficial effect of the 5 mg twice daily dose has been demonstrated: after 1 month of treatment with 5 mg twice daily, total exercise duration at the trough of drug activity increases by approximately 1 minute, and with further treatment over 3 months and dose escalation to 7.5 mg twice daily, by an additional 25 seconds. Ivabradine provides antianginal and anti-ischemic benefits in patients aged 65 years and older. The efficacy of 5 mg and 7.5 mg twice daily is approximately equal based on all study results. According to parameters of exercise tolerance testing (total exercise duration, time to onset of angina-limiting symptoms, time to onset of angina, and time to 1 mm ST-segment depression), the efficacy of 5 mg and 7.5 mg twice daily is approximately equivalent and confirmed by a reduction in angina attacks by approximately 70%. The twice-daily dosing regimen ensures consistent ivabradine effect over 24 hours.

When used as an add-on to 50 mg atenolol once daily, ivabradine demonstrates additional efficacy across all parameters of exercise tolerance testing at the trough of drug activity (12 hours after oral administration).

In contrast, ivabradine does not show additional efficacy in combination with amlodipine at the trough of drug activity (12 hours after oral administration), but demonstrates additional efficacy at peak activity (3–4 hours after oral administration).

Ivabradine maintains full efficacy throughout the entire treatment period of 3 or 4 months. There is no evidence of pharmacological tolerance (loss of efficacy) or rebound effect after abrupt discontinuation of the drug. Antianginal and anti-ischemic effects of ivabradine are associated with dose-dependent reduction in heart rate and significant reduction in the rate-pressure product (heart rate × systolic blood pressure) at rest and during physical exertion. The effect on blood pressure and peripheral vascular resistance is minimal and clinically insignificant.

In patients who have taken ivabradine for at least 1 year, a sustained reduction in heart rate is observed. No influence on glucose or lipid metabolism has been observed.

The antianginal and anti-ischemic action of ivabradine is preserved in patients with diabetes, and the safety profile is the same as in the general patient population. Specific ophthalmological studies 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, have demonstrated absence of retinal toxicity.

Use in pediatrics

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 3 to 18 years with body weight less than 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, the dose was subsequently 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 heart rate 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 the 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.

The long-term effect of ivabradine on growth, pubertal and general development, as well as long-term efficacy of ivabradine in reducing cardiovascular morbidity and mortality in children, has 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 in vivo does not demonstrate bioconversion. The main active metabolite of ivabradine in the human body is its N-desmethylated derivative.

Absorption and bioavailability. Ivabradine is rapidly and almost completely absorbed after oral administration and reaches peak plasma concentration within 1 hour when taken on an empty stomach. The absolute bioavailability of film-coated tablets is approximately 40% due to presystemic metabolism in the intestine and liver.

Food intake delays absorption by approximately 1 hour and increases plasma exposure by 20–30%. To reduce intra-individual variability in drug exposure, tablets are recommended to be taken with food.

Distribution. Approximately 70% of ivabradine is bound to plasma proteins. The volume of distribution at steady state is nearly 100 L. The maximum plasma concentration after long-term use of recommended doses of 5 mg twice daily is 22 ng/mL (coefficient of variation – 29%). The mean steady-state plasma concentration is 10 ng/mL (coefficient of variation – 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 is the N-desmethylated derivative (S 18982), with exposure approximately 40% of that of the parent substance. This active metabolite is also metabolized via CYP3A4. Ivabradine has low chemical affinity for CYP3A4, does not stimulate or inhibit it to a clinically significant extent, and therefore does not significantly alter CYP3A4 metabolism or its plasma concentration. However, potent inhibitors and inducers of CYP3A4 may substantially affect plasma concentrations of ivabradine.

Elimination. The elimination half-life of ivabradine in plasma is 2 hours (70–75% of the area under the pharmacokinetic curve), and the effective half-life is 11 hours. 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 drug 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

Elderly patients: No pharmacokinetic differences (AUC and C_max) have been observed between elderly patients (≥65 years), very elderly patients (≥75 years), and the general patient population.

Renal impairment: Since renal clearance accounts for only a minor fraction (approximately 20%) of the total clearance of ivabradine and its main metabolite S 18982, the impact of renal impairment (creatinine clearance from 15 to 60 mL/min) on the pharmacokinetics of the drug is minimal.

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

Children: The pharmacokinetic profile of ivabradine when administered according to an age- and weight-adjusted dosing regimen 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 that heart rate decreases almost linearly with increasing plasma concentrations of ivabradine and S 18982 at doses of 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 pharmacokinetic/pharmacodynamic relationship of ivabradine in children aged 6 months to 18 years is similar to that in adults.

Clinical characteristics.

Indications.

Symptomatic treatment of chronic stable angina.

IVAB-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 to 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.
• Sick sinus 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 P450 3A4 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 enhance QT interval prolongation. If combination therapy is necessary, careful monitoring of cardiac activity should be performed throughout treatment.

Combinations requiring caution in use.

Diuretics (thiazide and loop diuretics). Hypokalemia may increase the risk of arrhythmia. Ivabradine may cause bradycardia, and its combination with hypokalemia may provoke severe arrhythmia, particularly in patients with long QT syndrome, 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 or plasma concentrations of other CYP3A4 substrates (weak, moderate, or 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 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. 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 doubles ivabradine exposure. Therefore, consumption of grapefruit juice should be limited during ivabradine treatment.

Combinations requiring caution in use.

Other 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, St. John's wort (Hypericum perforatum). Concomitant use of these drugs with ivabradine may lead to reduced concentration and efficacy of ivabradine, so dose adjustment of ivabradine may be necessary. When ivabradine 10 mg twice daily was co-administered with St. John's wort, ivabradine concentration decreased by half. Use of St. John's wort should be avoided during ivabradine treatment.

Other combinations. The following drugs do not have clinically significant effects 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. Additionally, ivabradine did not exert clinically significant effects on the pharmacokinetics of simvastatin, amlodipine, and lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin and warfarin, or on the pharmacodynamics of aspirin. The use of combinations with ivabradine in the usual therapeutic regimen is safe with the following drugs: angiotensin-converting enzyme inhibitors, angiotensin II antagonists, diuretics, antimineralocorticoid agents, short- and long-acting nitrates, hydroxymethylglutaryl-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, as treatment with ivabradine has not demonstrated a beneficial effect on reducing the risk of cardiovascular events (such as myocardial infarction or fatal cardiovascular events) (see section "Pharmacodynamics").

Heart rate measurement. Given the potential for significant fluctuations in heart rate (HR), serial HR measurements, 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 HR, especially if HR decreases below 50 beats/min, or after dose reduction (see section "Dosage and administration").

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

The risk of developing atrial fibrillation is increased in patients taking ivabradine (see section "Adverse reactions"). Atrial fibrillation occurs more frequently in patients who are also receiving 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), with ECG monitoring if clinically indicated (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 balance 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 under close surveillance.

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 beats/min (see section "Contraindications").

If during treatment the resting heart rate decreases below 50 beats/min 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 beats/min 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 possible 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 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 in combination with nitrates and dihydropyridine calcium channel blockers, such as amlodipine, has not been evaluated. The potential for enhanced efficacy of ivabradine when used in combination with dihydropyridine calcium channel blockers has not been established.

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 sinus rhythm during pharmacological cardioversion while taking ivabradine has not been proven. However, due to insufficient data, non-emergency direct current cardioversion should not be performed earlier than 24 hours after the last dose of ivabradine.

Ivabradine should be avoided in patients with congenital prolonged QT interval or those taking drugs that prolong the QT interval. If ivabradine must be prescribed to such patients, careful cardiological monitoring is required. Heart rate reduction 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 treatment adjustments. In clinical trials, more episodes of blood pressure elevation were observed in patients receiving ivabradine (7.1%) 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. Blood pressure should be monitored at regular intervals when changes in therapy are introduced in patients with CHF receiving ivabradine (see section "Adverse reactions").

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

Use during pregnancy or breastfeeding.

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

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 passes into breast milk. Therefore, the drug is contraindicated for women who are breastfeeding. Women requiring ivabradine treatment 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 affect reaction speed when driving or operating machinery.

It has been established that ivabradine does not affect the ability to drive or operate machinery. However, during post-marketing surveillance, cases of impaired driving ability due to visual symptoms have been reported. Ivabradine may cause transient visual phenomena, mostly phosphenes, which typically occur following a sudden change 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.

Administer twice daily: in the morning and in the evening, during meals.

The tablet of IVAB-5® can be divided into equal doses.

Symptomatic treatment of chronic stable angina.

Decisions regarding initiation of treatment or dose titration are recommended to be made based on results of serial heart rate (HR) measurements, 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 there is no improvement in angina symptoms within 3 months after initiation of treatment, ivabradine therapy should be discontinued.

Additionally, discontinuation of therapy should be considered if symptomatic response 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 (½ tablet of IVAB-5® 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 a physician experienced in managing CHF.

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

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

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 tablet of IVAB-5® twice daily). If further reduction of HR is required, the dose may be gradually increased.

Patients with renal impairment. Patients with creatinine clearance > 15 mL/min do not require dose adjustment. Due to insufficient data, ivabradine should be used with caution in patients with creatinine clearance < 15 mL/min.

Patients with hepatic impairment. Patients with mild hepatic impairment do not require dose adjustment. Ivabradine should be administered 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").

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 forms of bradycardia require symptomatic treatment in specialized 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 following adverse reactions 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); unknown (cannot be estimated from the available data).

System of organs	Frequency	Term
Blood and lymphatic system disorders	Uncommon	Eosinophilia
Metabolism and nutrition disorders	Uncommon	Elevated plasma uric acid levels
Nervous system disorders	Common	Headache, usually during the first month of treatment Dizziness, likely related to bradycardia
	Uncommon*	Syncope, likely related to bradycardia
Eye disorders	Very common	Visual phenomena (phosphenes)
	Common	Blurred vision
	Uncommon*	Diplopia, visual disturbances
Ear and labyrinth disorders	Uncommon	Vertigo
Cardiac disorders	Common	Bradycardia, first-degree atrioventricular block (on ECG – prolonged PQ interval), ventricular extrasystoles, atrial fibrillation
	Uncommon	Palpitations, ventricular extrasystoles
	Very rare	Second- and third-degree atrioventricular 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 cramps
General disorders	Uncommon*	Asthenia, likely related to bradycardia; fatigue, likely related to bradycardia
	Rare	Malaise, likely related to bradycardia
Investigations	Uncommon	Elevated plasma creatinine levels; prolonged PQ interval on ECG

* 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 a temporary increase in brightness within a limited area of the visual field. Typically, their occurrence is triggered by a sudden change in light intensity. Phosphenes have also been described as glare, image decomposition (stroboscopic and kaleidoscopic effects), bright colored flashes, or multiple images (retinal persistence). The first episodes of phosphenes usually occur within the first 2 months of treatment and may recur later. Overall, phosphenes were reported as mild to moderate in severity. All cases of phosphenes resolved either during or after discontinuation of treatment, 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. In 0.5% of patients, severe bradycardia occurred with a heart rate of 40 beats per minute or lower.

In clinical studies, 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 of at least 3 months' duration 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 placebo group, corresponding to a relative risk of 1.26 (95% confidence interval: 1.15–1.39).

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows 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. 2 years.

Storage conditions. Store in the original packaging, at temperatures not exceeding 25°C, in a place inaccessible to children.

Packaging. 14 tablets in a blister pack, 2 blisters in a cardboard package (package No. 28).

Prescription status. Prescription only.

Manufacturer.

Bafna Pharmaceuticals Ltd., India / Bafna Pharmaceuticals Ltd., India.

Manufacturer's address and location of manufacturing site.

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

Marketing authorization holder. SCAN BIOTECH LTD, India / SCAN BIOTECH LTD, India.

Address of the marketing authorization holder.

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