Ivaswift 7.5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IVASWIFT 5 (IVASWIFT 5) IVASWIFT 7.5 (IVASWIFT 7.5)

Composition:

Active substance: ivabradine;

One film-coated tablet contains ivabradine oxalate equivalent to 5 mg or 7.5 mg of ivabradine;

Excipients: microcrystalline cellulose, crospovidone, colloidal anhydrous silicon dioxide, hydrogenated castor oil;

Film coating: Opadry Orange 03A530007 (hypromellose, microcrystalline cellulose, titanium dioxide (E 171), purified stearic acid, yellow iron oxide (E 172), red iron oxide (E 172)), carnauba wax.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

IVASWIFT 5: pale pink, elongated-shaped, biconvex, film-coated tablets with a break line on one side and smooth on the other side;

IVASWIFT 7.5: pale pink, curved triangular-shaped, biconvex, film-coated tablets, smooth on both sides.

Pharmacotherapeutic group. Cardiac preparations. Other cardiac preparations.
ATC code C01EB17.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

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

Ivabradine may also interact with Ih currents in the retinal cells, which are structurally similar to the If currents in the cardiac sinoatrial node. This underlies the development of transient visual disturbances due to reduced retinal response to bright light stimuli. Under triggering conditions (sudden changes in lighting), partial inhibition of Ih currents by ivabradine may lead to unexpected visual phenomena in patients. These 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 selective, dose-dependent reduction of HR. Analysis of HR reduction with ivabradine doses < 20 mg twice daily showed a tendency toward a plateau effect, reducing the risk of severe bradycardia < 40 beats per minute (bpm) (see section "Adverse reactions").

At recommended therapeutic doses (5–7.5 mg twice daily), HR is reduced by approximately 10 bpm 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 has been demonstrated in five double-blind, randomized studies (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 demonstrated efficacy based on exercise testing parameters over 3–4 weeks of treatment. Additional benefits of increasing the ivabradine dose to 7.5 mg twice daily were demonstrated in a controlled comparative study versus atenolol: exercise duration increased by 1 minute after one month of treatment with ivabradine 5 mg twice daily; after three months of dose escalation to 7.5 mg twice daily, exercise duration further increased by nearly 25 seconds. 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 development of 1 mm ST-segment depression) and was associated with approximately a 70% reduction in the number of angina attacks. The twice-daily dosing regimen of ivabradine provided stable and effective action over 24 hours.

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

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

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

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

In the large-scale BEAUTIFUL study assessing morbidity and mortality, involving 10,917 patients with ischemic heart disease and left ventricular dysfunction (LVEF < 40%), ivabradine was administered on top of optimal background therapy (86.9% of patients received β-blockers). The primary efficacy endpoint (primary composite endpoint) was the total number of cardiovascular deaths, hospitalizations due to myocardial infarction (MI), and hospitalizations due to onset or worsening of heart failure (HF). The study showed no significant difference in reduction of the primary composite endpoint between ivabradine and placebo groups, either in the overall population (relative risk [RR] 1.00; p = 0.94) or in the subgroup analysis of patients with HR ≥ 70 bpm (RR 0.91; p = 0.17). However, in the group of patients with HR ≥ 70 bpm receiving ivabradine, the rate of hospitalizations due to fatal and non-fatal MI decreased by 36% (p = 0.001), and coronary revascularization procedures decreased by 30% (p = 0.016).

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

In the large-scale SIGNIFY study assessing morbidity and mortality, involving 19,102 patients with ischemic heart disease without clinical signs of heart failure (LVEF > 40%), ivabradine was administered on top of optimal background therapy. In this study, a higher therapeutic dose than approved 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 primary endpoint consisting of total cardiovascular deaths or non-fatal myocardial infarction. The study found no difference in the incidence of the composite primary endpoint between the ivabradine and placebo groups (RR 1.08; p = 0.197). Bradycardia was observed in 17.9% of patients in the ivabradine group (2.1% in the placebo group). During the study, 7.1% of patients received verapamil, diltiazem, or strong CYP3A4 inhibitors.

A small but statistically significant increase in the incidence of the composite primary endpoint 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) (3.4% per year vs. 2.9%, RR 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) (RR 1.11; p = 0.110).

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

SHIFT was a multicenter, international, randomized, double-blind, placebo-controlled morbidity and mortality study involving 6505 adult patients with stable chronic heart failure (CHF) and left ventricular dysfunction (LVEF ≤ 35%). The study included patients with systolic CHF in NYHA functional classes II–IV (New York Heart Association classification) of duration ≥ 4 weeks and resting HR ≥ 70 bpm.

Patients received standard therapy, including β-blockers (89%), ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and aldosterone antagonists (60%). In the ivabradine group, 67% of patients received the drug at a dose of 7.5 mg twice daily. Median follow-up was 22.9 months. Treatment with ivabradine was associated with an average reduction in HR of 15 bpm compared to the baseline of 80 bpm. The difference in HR between the ivabradine and placebo groups was 10.8 bpm after 28 days, 9.1 bpm at 12 months, and 8.3 bpm at 24 months.

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

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

	Ivabradine (N = 3241) n (%)	Placebo (N = 3264) n (%)	HR (95 % CI)	p-value
Primary composite endpoint	793 (24.47)	937 (28.71)	0.82 (0.75–0.90)	< 0.0001
Components of primary endpoint: cardiovascular death; hospitalization for worsening heart failure	449 (13.85) 514 (15.86)	491 (15.04) 672 (20.59)	0.91 (0.80–1.03) 0.74 (0.66–0.83)	0.128 < 0.0001
Other secondary endpoints: all-cause mortality; heart failure–related mortality; hospitalizations for any cause; hospitalizations for cardiovascular disease	503 (15.52) 113 (3.49) 1231 (37.98) 977 (30.15)	552 (16.91) 151 (4.63) 1356 (41.54) 1122 (34.38)	0.90 (0.80–1.02) 0.74 (0.58–0.94) 0.89 (0.82–0.96) 0.85 (0.78–0.92)	0.092 0.014 0.003 0.0002

A reduction in the occurrence of the combined primary endpoint was observed independently of sex, NYHA class, ischemic or non-ischemic etiology of heart failure, and the presence of comorbid conditions (diabetes mellitus or arterial hypertension) in patient history.

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

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

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

In a randomized, placebo-controlled study involving 97 patients (data obtained from specialized ophthalmological examinations aimed at documenting the function of cone and rod systems and the ascending visual pathway, using electroretinography, static and kinetic visual field testing, color vision, and visual acuity), no retinal toxicity was demonstrated in patients treated with ivabradine for chronic stable angina over 3 years.

Pharmacokinetics.

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

Absorption and bioavailability. After oral administration, ivabradine is rapidly and almost completely absorbed. When administered on an empty stomach, maximum plasma concentration (Cmax) is reached approximately within 1 hour. The absolute bioavailability of ivabradine is nearly 40%, due to first-pass metabolism in the gut and liver. Taking the drug with food delays absorption by approximately 1 hour and increases plasma concentration by 20–30%. To minimize intra-individual fluctuations in plasma concentrations of ivabradine, the drug is recommended to be taken with meals (see section "Dosage and administration").

Distribution. Approximately 70% of ivabradine is bound to plasma proteins. The volume of distribution at steady state is about 100 L. With chronic administration of the recommended initial dose of 5 mg twice daily, the Cmax in plasma is approximately 22 ng/mL (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) system through oxidation. The main active metabolite of ivabradine is its N-desmethyl derivative (S18982), whose concentration is about 40% of the ivabradine hydrochloride concentration. The main active metabolite is also metabolized by the CYP3A4 cytochrome system. Ivabradine has low affinity for CYP3A4, does not induce or inhibit it, and is therefore unlikely to alter CYP3A4 metabolism or its plasma concentration. However, CYP3A4 inhibitors and inducers can significantly affect ivabradine plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Special patient groups.

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

Renal impairment: the effect of renal impairment (creatinine clearance 15–60 mL/min) on ivabradine kinetics is minimal due to the small contribution of renal clearance (about 20%) to the total clearance of ivabradine and its main metabolite S18982 (see section "Dosage and administration").

Hepatic impairment: in patients with mild hepatic impairment, unbound AUC values for ivabradine and its main active metabolite were 20% higher than in patients with normal liver function. Data on ivabradine pharmacokinetics in patients with moderate hepatic impairment are limited; data in patients with severe hepatic impairment are lacking (see sections "Dosage and administration" and "Contraindications").

Pharmacokinetic/pharmacodynamic relationship. Analysis of the pharmacokinetic/pharmacodynamic relationship demonstrated a linear correlation between decreasing heart rate and increasing plasma concentrations of ivabradine and its active metabolite at doses of 15–20 mg twice daily. At higher doses, the reduction in heart rate becomes disproportionate to plasma ivabradine concentration and tends to plateau. High plasma concentrations of ivabradine may result from co-administration with strong CYP3A4 inhibitors, potentially leading to a significant decrease in heart rate; however, the risk is reduced when ivabradine is used in combination 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.

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

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

Treatment of chronic heart failure.

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

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Resting heart rate < 70 beats/min prior to initiation of treatment.
• Cardiogenic shock.
• Acute myocardial infarction.
• Severe arterial hypotension (blood pressure < 90/50 mm Hg).
• Severe hepatic impairment.
• Sinus node dysfunction (sick sinus syndrome).
• Sinoatrial block.
• Unstable or acute heart failure.
• Presence of a cardiac pacemaker (heart rate controlled exclusively by the pacemaker).
• Unstable angina.
• Third-degree atrioventricular (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 if the patient of childbearing potential does not use appropriate contraceptive measures (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions.

Unrecommended combinations.

Drugs that prolong the QT interval:

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

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

Combinations requiring precautions.

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

Pharmacokinetic interactions.

Cytochrome P450 3A4 (CYP3A4). Ivabradine is metabolized exclusively by the CYP3A4 enzyme and is a very weak inhibitor of this enzyme. It has been confirmed that ivabradine does not affect the metabolism or plasma concentrations of other CYP3A4 substrates (weak, moderate, or strong). Inhibitors and inducers of CYP3A4 are prone to interact with ivabradine, resulting in clinically significant effects on its metabolism and pharmacokinetics. Drug interaction studies have confirmed that CYP3A4 inhibitors increase plasma concentrations of ivabradine, while CYP3A4 inducers decrease them. Increased plasma concentrations of ivabradine may increase the risk of excessive bradycardia (see section "Special precautions for use").

Contraindicated combinations.

Concomitant 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/day) and josamycin (1 g twice daily) increase the average plasma concentration of ivabradine by 7–8 times.

Moderate CYP3A4 inhibitors. Specific studies in healthy volunteers and patients have shown that combining ivabradine with heart rate-lowering agents such as diltiazem and verapamil increases ivabradine concentration (by 2–3 times in terms of AUC) and causes an additional decrease in heart rate of 5 beats/min. Concomitant use of ivabradine with these drugs is contraindicated (see section "Contraindications").

Unrecommended combinations.

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

Combinations requiring precautions.

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

CYP3A4 inducers – rifampicin, barbiturates, phenytoin, St. John's wort (Hypericum perforatum). Concomitant use of these drugs with ivabradine may reduce ivabradine concentration and its efficacy, necessitating dose adjustment. When ivabradine 10 mg twice daily is used concomitantly with St. John's wort, ivabradine concentration is halved. 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. Studies have also demonstrated that ivabradine has no clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, or on the pharmacokinetics and pharmacodynamics of digoxin and warfarin, or on the pharmacodynamics of aspirin.

Phase III clinical trials have confirmed that ivabradine can be used concomitantly with ACE inhibitors, angiotensin II antagonists, β-blockers, diuretics, aldosterone antagonists, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetic agents, aspirin, and other antithrombotic agents.

Special precautions for use.

Special warnings.

Insufficient beneficial effect on clinical outcomes in patients with symptomatic chronic stable angina. Ivabradine is indicated only for symptomatic treatment of chronic stable angina, as treatment with ivabradine has not demonstrated a beneficial effect on reducing the risk of cardiovascular events (such as myocardial infarction or cardiovascular mortality) (see section «Pharmacodynamics»).

Heart rate measurement. Due to the potential for significant fluctuations in heart rate (HR), serial measurements of resting HR, 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 prescribed for the prevention or treatment of arrhythmias. If tachyarrhythmia (ventricular or supraventricular) develops during ivabradine therapy, continued administration of ivabradine is no longer appropriate. Therefore, ivabradine is not recommended for patients with atrial fibrillation or other types of arrhythmias affecting sinus node function.

The risk of developing atrial fibrillation is increased in patients taking ivabradine (see section «Adverse reactions»). Atrial fibrillation occurs more frequently in patients who are concurrently using amiodarone or potent class I antiarrhythmic drugs. Regular clinical monitoring is recommended during ivabradine treatment to enable early detection of atrial fibrillation (paroxysmal or persistent), with ECG monitoring if 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 promptly. If atrial fibrillation occurs during treatment, the benefit-risk balance of continuing ivabradine therapy should be carefully evaluated.

Patients with heart failure (HF), 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. Ivabradine is not recommended for these patients.

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

Combination with calcium channel blockers. Concomitant use of ivabradine with calcium channel blockers that reduce HR, such as verapamil or diltiazem, is contraindicated (see sections «Contraindications» and «Interaction with other medicinal products and other forms of interaction»). No reports of safety concerns have been received regarding the use of ivabradine with short- or long-acting nitrates or dihydropyridine calcium channel blockers (e.g., amlodipine). The additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been studied (see section «Pharmacodynamics»).

Chronic heart failure. When deciding to initiate ivabradine therapy in heart failure, the patient’s clinical status should be carefully 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 immediately after an acute stroke, as clinical studies have not included this patient group.

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. Ivabradine should be prescribed with caution in patients with retinitis pigmentosa.

Precautions during use.

Patients with arterial hypotension. Due to insufficient data on the use of ivabradine in patients with mild to moderate arterial hypotension, it should be administered with caution in such patients. Ivabradine 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 an increased risk of severe bradycardia upon restoration of sinus rhythm during pharmacological cardioversion in patients treated with ivabradine. However, due to insufficient data, non-emergency DC cardioversion should not be performed earlier than 24 hours after the last dose of ivabradine.

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

Patients with arterial hypertension requiring treatment adjustments. In the SHIFT study, 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 effect of ivabradine. Blood pressure should be monitored at regular intervals when treatment modifications are made in patients with chronic heart failure receiving ivabradine (see section «Adverse reactions»).

Excipients. The product contains hydrogenated castor oil, which may cause gastrointestinal discomfort and diarrhea.

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 lacking or limited. Animal studies have shown toxic effects of ivabradine on reproduction, as well as embryotoxic and teratogenic effects. The potential risk in humans is unknown. Therefore, ivabradine is contraindicated during pregnancy.

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

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

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

Ability to influence reaction speed when driving or operating machinery.

A targeted study in healthy volunteers demonstrated that ivabradine does not impair the ability to drive or operate machinery. However, 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 occurring in response to sudden changes in light intensity. This should be taken into account when driving, especially at night, or operating machinery.

Method of Administration and Dosage.

Ivabradine may be administered to adult patients.

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

The Ivaswift 5 mg tablet may be divided into equal doses.

The Ivaswift 7.5 mg tablet must not be divided.

Symptomatic treatment of chronic stable angina.

Decisions regarding initiation of treatment or dose titration are recommended to be 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, 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.

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

If during treatment resting HR decreases to < 50 bpm or the patient experiences symptoms of bradycardia (dizziness, weakness, arterial hypotension), the dose should be gradually reduced, including consideration of the lowest dose of 2.5 mg twice daily (½ tablet of Ivabradine 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 a physician experienced in the management of CHF.

The recommended initial dose of ivabradine is 5 mg twice daily. After a two-week treatment period, the dose may be increased to 7.5 mg twice daily if resting HR remains > 60 bpm during treatment, or reduced to 2.5 mg twice daily (½ tablet of Ivabradine 5 mg 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 be maintained unchanged.

If during treatment HR decreases to < 50 bpm or the patient experiences symptoms of bradycardia while receiving ivabradine 7.5 or 5 mg twice daily, the dose should be gradually reduced to the next lower dose. 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 dose.

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. For 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 Ivabradine 5 mg twice daily). If further HR reduction is needed, the dose may be gradually increased.

Renal impairment. Dose adjustment is not required in patients with creatinine clearance > 15 mL/min (see section "Pharmacokinetics"). Due to insufficient data, ivabradine should be used with caution in patients with creatinine clearance < 15 mL/min.

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

Children.

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

Overdose.

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

Adverse Reactions

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

The most common adverse reactions associated with ivabradine—visual phenomena (phosphenes) and bradycardia—are dose-dependent and related to its pharmacological mechanism of action.

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

Blood and lymphatic system disorders. Uncommon: eosinophilia.

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

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

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

Ear and labyrinth disorders. Uncommon: vertigo.

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

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

Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnea.

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

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

Musculoskeletal and connective tissue disorders. Uncommon: muscle spasms.

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

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

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

Description of selected adverse reactions.

Visual phenomena (phosphenes) were observed in 14.5% of patients as temporary increases in brightness within a limited area of the visual field. These typically occur in response to sudden changes in light intensity. Phosphenes have also been described as halos, image decomposition (stroboscopic and kaleidoscopic effects), bright colored flashes, or multiple images (retinal persistence). Phosphenes occur 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 discontinuation, with the majority (77.5%) resolving during therapy. Less than 1% of patients required changes in their usual activities or discontinuation of treatment due to phosphenes.

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

In the SIGNIFY 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 of at least 3 months' duration involving more than 40,000 patients demonstrated that the incidence of atrial fibrillation was 4.86% in patients receiving ivabradine compared to 4.08% in the placebo group, corresponding to a relative risk of 1.26 (95% confidence interval: 1.15–1.39).

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product registration is important. It allows 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 at temperatures not exceeding 30°C. Keep out of reach and sight of children.

Packaging.

14 tablets in a blister. 4 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Ind-Swift Limited.

Manufacturer's address and place of business.

Off. NH-21, Village Jawaharpur, Tehsil Dera Bassi, District S.A.S. Nagar (Mohali),
IN-140507, India.