Instructions Bravadin film-coated tablets 7.5 mg blister No. 28
Composition
active substance: ivabradine;
1 film-coated tablet contains 5 mg ivabradine, equivalent to 5.39 mg ivabradine hydrochloride, or 7.5 mg ivabradine, equivalent to 8.085 mg ivabradine hydrochloride;
excipients: lactose monohydrate, magnesium stearate, corn starch, maltodextrin, colloidal anhydrous silicon dioxide, hypromellose;
film coating: hypromellose, titanium dioxide (E 171), talc, propylene glycol, iron oxide yellow (E 172), iron oxide red (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties:
5 mg: pale pinkish-orange, rectangular-shaped, slightly biconvex, film-coated tablets with a score on one side;
7.5 mg: pale pinkish-orange, round, slightly biconvex, film-coated tablets with a beveled edge.
Pharmacotherapeutic group
Cardiological drugs. Other cardiological drugs. ATX code C01E B17.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
Ivabradine is a substance that reduces heart rate (HR) by acting on the cardiac pacemaker by selective and specific inhibition of the If current, which controls spontaneous diastolic depolarization at the level of the sinus node, regulating heart rate. Ivabradine acts exclusively on the sinus node and does not affect intraatrial, atrioventricular and intraventricular conduction, myocardial contractility and ventricular repolarization.
Ivabradine may also interact with the retinal Ih current, which is structurally similar to the If current of the sinus node. This is the basis for the development of a temporary impairment of photoperception due to a decrease in the retinal response to bright light stimuli. In the presence of triggering circumstances (sudden change in lighting), partial inhibition of the Ih current by ivabradine may lead to the unexpected occurrence of visual phenomena in patients. Visual phenomena (phosphenes) manifest as a temporary increase in brightness in a limited area of the visual field (see section "Adverse reactions").
Pharmacodynamic effects
The main pharmacodynamic property of ivabradine is a selective dose-dependent reduction in heart rate. Analysis of the reduction in heart rate with ivabradine at doses < 20 mg twice daily showed a tendency towards a plateau effect, which reduces the risk of severe bradycardia < 40 beats/min (see section 4.8).
When using ivabradine in recommended therapeutic doses (5–7.5 mg 2 times a day), the heart rate decreases by approximately 10 beats/min at rest and during exercise. This reduces cardiac work and myocardial oxygen consumption. Ivabradine does not affect intracardiac conduction, myocardial contractility (no negative inotropic effect) and ventricular repolarization:
In clinical electrophysiological studies, ivabradine did not affect atrioventricular or intraventricular conduction or the corrected QT interval;
In patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30–45%), ivabradine did not show any negative effect on LVEF.
Clinical efficacy and safety
Studies have proven the antianginal and antiischemic efficacy of ivabradine.
These properties of ivabradine have been confirmed in patients over 65 years of age. The efficacy of ivabradine at doses of 5 and 7.5 mg twice daily was consistent across all studies in terms of exercise testing (total duration of exercise, time to onset of limiting angina, time to angina attack, time to 1 mm ST segment depression) and was accompanied by a reduction in the number of angina attacks by approximately 70%. The ivabradine twice daily dosing regimen provided a stable efficacy over 24 hours.
In a study of ivabradine, which was administered in addition to atenolol at a dose of 50 mg per day, additional efficacy was observed in all indicators of exercise tests 12 hours after administration.
Efficacy studies have shown that the efficacy of ivabradine is fully maintained over 3 or 4 months of treatment. In these studies, no cases of pharmacological tolerance (loss of efficacy) or withdrawal effects were observed after abrupt discontinuation of treatment. The antianginal and antiischemic efficacy of ivabradine was associated with a dose-dependent reduction in heart rate and a significant reduction in the double product (DP), which reflects myocardial oxygen demand at rest and during exercise (DP = heart rate × systolic blood pressure). The effect of ivabradine on blood pressure (BP) and peripheral vascular resistance was minimal and of no clinical significance.
Long-term studies have confirmed the sustained effect of ivabradine on reducing heart rate and demonstrated the absence of effects of ivabradine on glucose and lipid metabolism.
In a large study of morbidity and mortality in patients with coronary heart disease and left ventricular dysfunction (LVEF < 40%), ivabradine was administered on top of optimal background therapy (86.9% of patients received beta-blockers). The primary efficacy endpoint (primary composite endpoint) was the composite of cardiovascular mortality, hospitalization for myocardial infarction, and new or worsening heart failure (HF). The study showed no significant difference in the reduction of the primary composite endpoint between the ivabradine and placebo groups.
In a large study of morbidity and mortality in patients with coronary heart disease without clinical signs of heart failure (LVEF > 40%), ivabradine was administered on top of optimal background therapy. This study used a higher-than-approved dose regimen (starting dose of 7.5 mg twice daily (5 mg twice daily for patients aged 75 years and older) and titrated to 10 mg twice daily). The primary efficacy endpoint was the composite primary endpoint, which was the total number of cardiovascular mortality or non-fatal myocardial infarction. The study did not show a difference in the incidence of the composite primary endpoint between the ivabradine group and the placebo group. 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 were receiving verapamil, diltiazem, or strong CYP3A4 inhibitors.
A small statistically significant increase in the incidence of the composite primary endpoint was observed in a prespecified subgroup of patients with Canadian Cardiovascular Society (CCS) class II or higher angina (3.4% events per year vs. 2.9%); however, no such effect was observed in the subgroup of the general population with CCS class ≥ I angina. The use of a higher than approved dose in the study may partly explain the results.
The morbidity and mortality study enrolled patients with systolic chronic heart failure (CHF) functional classes II–IV [according to the New York Heart Association (NYHA) classification of chronic heart failure] of ≥ 4 weeks duration, left ventricular dysfunction (LVEF ≤ 35%) and resting heart rate ≥ 70 beats/min.
Patients received standard therapy, including beta-blockers (89%), angiotensin-converting enzyme 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. Treatment with ivabradine was associated with a mean reduction in heart rate of 15 beats/min from a baseline of 80 beats/min.
This study demonstrated a clinically and statistically significant reduction in the risk of cardiovascular mortality and hospitalization for worsening heart failure within the first 3 months of therapy.
The reduction in the risk of mortality was observed regardless of gender, NYHA class, ischemic or non-ischemic etiology of HF, and the presence of a comorbid disease (diabetes mellitus or arterial hypertension) in the patient's history.
This study demonstrated a significant reduction in the risk of mortality in the overall group of patients treated with beta-blockers. In the subgroup of patients with heart rate ≥ 75 beats/min who received beta-blockers at recommended doses, there was no statistically significant effect on the combined primary endpoint and other secondary endpoints, including hospitalization for worsening HF or death from HF.
28% of patients in the ivabradine group had a significant improvement in functional class (according to NYHA classification) compared to 24% of patients in the placebo group.
Controlled ophthalmological studies of the photoreceptor system and visual pathway (electroretinograms, static and dynamic fields, color perception and visual activity) in 97 patients treated with ivabradine for chronic stable angina for 3 years did not show any retinal toxicity of ivabradine.
Pharmacokinetics.
Under physiological conditions, ivabradine is rapidly released and has a high water solubility (> 10 mg/ml). Ivabradine is the S-enantiomer, which has not been shown to undergo bioconversion in vivo. The main active metabolite of ivabradine is the N-desmethylated derivative.
Absorption and bioavailability
After oral administration, ivabradine is rapidly and almost completely absorbed. When administered in the fasting state, the maximum concentration (Cmax) in the blood plasma is reached after approximately 1 hour. The absolute bioavailability of ivabradine is approximately 40%, which is due to the effect of the first passage through the digestive tract and liver. Taking the drug simultaneously with food slows down the absorption by approximately 1 hour and increases the concentration in the blood plasma by
20–30%. To avoid fluctuations in ivabradine plasma concentrations, it is recommended to take the drug with food (see section “Method of administration and dosage”).
Ivabradine is approximately 70% bound to plasma proteins. The volume of distribution at steady state is approximately 100 l. With long-term use of the recommended starting dose of 5 mg twice daily, Cmax in plasma is approximately 22 ng/ml (CV = 29%). The mean plasma concentration at steady state is 10 ng/ml (CV = 38%).
Biotransformation
Ivabradine is extensively metabolised in the liver and intestine by oxidation by the cytochrome P450 3A4 (CYP3A4) system. The main active metabolite of ivabradine is its N-desmethyl derivative (S18982), the concentration of which is 40% of that of ivabradine hydrochloride. The main active metabolite is also metabolised by the cytochrome CYP3A4 system. Ivabradine has a low affinity for CYP3A4, does not activate or inhibit it, and is therefore unlikely to alter CYP3A4 metabolism or its plasma concentration. However, inhibitors and inducers of CYP3A4 may significantly affect the plasma concentration of ivabradine (see section 4.5).
Breeding
The mean elimination half-life of ivabradine is 2 hours (70-75% of the area under the curve of the blood concentration-time curve [AUC]), and the effective half-life is 11 hours. The total clearance of ivabradine is 400 ml/min, and the renal clearance of ivabradine is 70 ml/min. Metabolites are excreted equally in urine and feces. Approximately 4% of the active substance is excreted unchanged in urine.
Linearity/nonlinearity
The kinetics of ivabradine in doses of 0.5-24 mg are linear.
Special patient groups
Elderly patients (65–75 years of age): pharmacokinetic parameters (AUC and Cmax) in patients of this age group do not differ from the pharmacokinetic parameters of the general patient population (see section “Method of administration and dosage”).
Renal impairment: The effect of renal impairment (creatinine clearance 15-60 ml/min) on the pharmacokinetics of ivabradine is minimal given the small proportion of renal clearance (approximately 20%) of the total clearance of ivabradine and its main metabolite S18982 (see section 4.2).
Hepatic impairment: In patients with mild hepatic impairment (up to 7 on the Child-Pugh scale), the unbound AUC of ivabradine and the main active metabolite were 20% higher than in patients with normal hepatic function. Limited data on the pharmacokinetics of ivabradine in patients with moderate hepatic impairment; no data are available in patients with severe hepatic impairment (see sections 4.3 and 4.2).
Pharmacokinetics/pharmacodynamics relationship
Analysis of the pharmacokinetic-pharmacodynamic relationship demonstrated a linear relationship between the decrease in heart rate and the increase in plasma concentrations of ivabradine and its active metabolite at doses of 15-20 mg twice daily. At higher doses, the decrease in heart rate becomes disproportionate to the plasma concentration of ivabradine and tends to plateau. High plasma concentrations of ivabradine may be due to the use of ivabradine in combination with strong CYP3A4 inhibitors, which may lead to a significant decrease in heart rate, but the risk is reduced when ivabradine is used in combination with moderate CYP3A4 inhibitors (see sections “Contraindications”, “Interaction with other medicinal products and other forms of interaction” and “Special warnings and precautions for use”).
Indication
Symptomatic treatment of chronic stable angina.
Ivabradine is indicated for the symptomatic treatment of chronic stable angina in adult patients with coronary artery disease, normal sinus rhythm and a heart rate ≥ 70 beats per minute (bpm).
The drug should be prescribed:
patients who have contraindications or restrictions to the use of beta-blockers;
in combination with beta-blockers in patients whose condition is not adequately controlled with the optimal dose of beta-blockers.
Treatment of chronic heart failure.
Ivabradine is indicated for the treatment of chronic heart failure class II-IV (NYHA classification) with systolic dysfunction in adult patients with sinus rhythm and heart rate ≥ 75 beats/min in combination with standard therapy, including beta-blocker therapy, or when beta-blockers are contraindicated or poorly tolerated (see section 5.1).
Contraindication
Hypersensitivity to the active substance or to any of the excipients.
Resting heart rate < 70 beats/min before treatment.
Cardiogenic shock.
Acute myocardial infarction.
Severe arterial hypotension (BP < 90/50 mm Hg).
Severe liver failure.
Sick sinus syndrome.
Sinoatrial block.
Unstable or acute heart failure.
The patient has an artificial pacemaker (heart rate is controlled exclusively with the help of an artificial pacemaker).
Unstable angina.
Combination with potent P450 3A4 inhibitors: antifungals - azole derivatives (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin for oral use, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see sections "Pharmacokinetics" and "Interaction with other medicinal products and other types of interactions").
Concomitant use with verapamil or diltiazem, which are moderate CYP3A4 inhibitors that have heart rate-lowering properties (see section "Interaction with other medicinal products and other types of interactions").
Pregnancy, lactation. Also contraindicated in women of reproductive age who do not use adequate contraception (see section "Use during pregnancy or lactation").
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, ibutilide, amiodarone.
Non-cardiovascular: pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin.
The concomitant use of ivabradine and cardiovascular and non-cardiovascular drugs that prolong the QT interval should be avoided, as the decrease in heart rate may increase the QT interval prolongation. If such a combination is necessary, careful cardiac monitoring should be ensured (see section 4.4).
Combinations that require caution when used
Saluretics (thiazide and loop)
Hypokalemia increases the risk of arrhythmia. Ivabradine may cause bradycardia, which, in the presence of hypokalemia, may precipitate severe arrhythmias, especially in patients with congenital or drug-induced long QT syndrome.
Pharmacokinetic interactions
Ivabradine is metabolized only by CYP3A4 and is a very weak inhibitor of this cytochrome. It has been confirmed that ivabradine does not affect the metabolism and plasma concentrations of other CYP3A4 derivatives (weak, moderate and strong). CYP3A4 inhibitors and inducers may interact with ivabradine, which has a clinically significant effect on its metabolism and pharmacokinetics. Drug interaction studies have confirmed that CYP3A4 inhibitors increase ivabradine plasma concentrations, while CYP3A4 inducers decrease them. Increased ivabradine plasma concentrations increase the risk of excessive bradycardia (see section 4.4).
Contraindicated combinations
Potent CYP3A4 inhibitors
Concomitant use of ivabradine and such strong CYP3A4 inhibitors as azole antifungals (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 daily) and josamycin (1 g twice daily) increase the average plasma concentration of ivabradine by 7-8 times.
Moderate CYP3A4 inhibitors
Special studies in patients have shown that the combination of ivabradine with heart rate lowering drugs such as diltiazem and verapamil leads to an increase in ivabradine concentrations (2-3 times in terms of AUC) and an additional decrease in heart rate by 5 beats/min. The simultaneous use of ivabradine and these drugs is contraindicated (see section "Contraindications").
Not recommended combinations
Concomitant intake of grapefruit juice and ivabradine increases the plasma concentration of the latter by 2-fold. Therefore, grapefruit juice should be avoided.
Combinations that require caution when used
Moderate CYP3A4 inhibitors (e.g. fluconazole) Concomitant use of ivabradine with other moderate CYP3A4 inhibitors (e.g. fluconazole) may be initiated at 2.5 mg twice daily if resting heart rate is > 70 beats/min. Heart rate should be monitored. CYP3A4 inducers; CYP3A4 inducers (rifampicin, barbiturates, phenytoin, St. John's wort [Hypericum perforatum])
The simultaneous use of these drugs with ivabradine may lead to a decrease in the concentration of the latter and a decrease in its effectiveness, as a result of which there will be a need to adjust the dose of ivabradine. When ivabradine is used simultaneously at a dose of 10 mg 2 times a day and St. John's wort, the concentration of ivabradine decreases by 2 times. Therefore, the use of St. John's wort should be avoided during treatment with ivabradine.
Other combinations
The possibility of using ivabradine with angiotensin-converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, aldosterone antagonists, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetic agents, aspirin and other antithrombotic drugs has been confirmed.
Application features
Special precautions
Insufficient beneficial effect on clinical outcomes in patients with symptomatic chronic stable angina
Ivabradine is indicated only for the symptomatic treatment of chronic stable angina pectoris, as treatment with ivabradine has not been shown to reduce the risk of cardiovascular complications such as myocardial infarction or cardiovascular death (see section 5.1).
Heart rate measurement
Given the possibility of significant heart rate variability, resting heart rate should be determined before starting treatment and serial heart rate measurements, ECG or 24-hour ambulatory monitoring should be performed if titration of ivabradine is necessary. This also applies to patients with low heart rate, especially if the heart rate decreases to < 50 beats/min or after dose reduction (see section 4.2).
Arrhythmias
Ivabradine should not be prescribed for the prevention or treatment of arrhythmias. If a patient develops tachyarrhythmia (ventricular or supraventricular) during ivabradine therapy, ivabradine is no longer appropriate. Therefore, ivabradine is not recommended for use in patients with atrial fibrillation and other types of arrhythmias that affect sinus node function.
Patients taking ivabradine are at increased risk of developing atrial fibrillation (see section 4.8). Atrial fibrillation occurs more frequently in patients concomitantly taking amiodarone or potent class I antiarrhythmic drugs. During treatment with ivabradine, regular clinical monitoring of patients is recommended for the early detection of atrial fibrillation (paroxysmal or persistent) with ECG monitoring if clinically indicated (worsening of angina symptoms, palpitations, irregular pulse). Patients should be warned about the symptoms of atrial fibrillation and to inform their doctor if they occur. If atrial fibrillation occurs during treatment, the appropriateness of continuing ivabradine therapy should be carefully weighed against the benefit/risk ratio.
Patients with CHF, intraventricular conduction disorders (left bundle branch block, right bundle branch block) and ventricular desynchronization should be closely monitored.
Patients with second-degree AV block
Ivabradine is not recommended for such patients.
Patients with low heart rate
Ivabradine should not be administered to patients with a resting heart rate < 70 beats/min prior to initiation of treatment (see section 4.3). If during therapy the resting heart rate decreases to < 50 beats/min or the patient develops symptoms of bradycardia (dizziness, weakness, hypotension), the dose should be gradually reduced or the drug should be discontinued if the heart rate remains < 50 beats/min or symptoms of bradycardia persist (see section 4.4).
Combination with calcium channel blockers
The use of ivabradine with calcium channel blockers that reduce heart rate, such as verapamil or diltiazem, is contraindicated (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”). There have been no reports of the dangers of using ivabradine with short- and long-acting nitrates, dihydropyridine calcium channel blockers (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 whether to start ivabradine therapy in HF, the patient's condition should be assessed. Treatment is only possible if HF is stable. Ivabradine should be used with caution in patients with CHF functional class IV (according to the NYHA classification) due to the limited amount of data in this group of patients.
Stroke
Ivabradine is not recommended for use in patients immediately after a stroke, as studies have not been conducted in this group of patients.
Effects on the organs of vision
There is evidence that ivabradine affects retinal function. There is no evidence of long-term retinal toxicity with ivabradine (see section 5.1). If any unexpected visual impairment occurs, treatment should be discontinued. Ivabradine should be used with caution in patients with retinitis pigmentosa.
Patients with arterial hypotension
Due to the lack of sufficient data on the use of ivabradine in patients with mild to moderate arterial hypotension, it should be used with caution in such patients. Ivabradine is contraindicated in patients with severe arterial hypotension (BP < 90/50 mm Hg) (see section "Contraindications").
There is no evidence of a risk of severe bradycardia in patients treated with ivabradine after pharmacological cardioversion to restore sinus rhythm. However, due to the lack of sufficient data, it is recommended that DC cardioversion (which is not urgent) be performed no earlier than 24 hours after the last dose of ivabradine.
Patients who have a congenital long QT interval or are taking drugs that prolong the QT interval
Ivabradine should be avoided in such patients (see section 4.5). If ivabradine is prescribed to these patients, close cardiac monitoring is recommended. The decrease in heart rate due to ivabradine may increase the QT interval prolongation associated with the occurrence of severe arrhythmias, especially torsades de pointes.
Patients with hypertension who require changes in treatment
In patients treated with ivabradine, more episodes of increased blood pressure (7.1%) were observed compared to patients treated with placebo (6.1%). These episodes occurred more often shortly after changes in the treatment of hypertension, were transient and did not affect the therapeutic effect of ivabradine. In case of changes in the treatment of patients with CHF while receiving ivabradine, blood pressure should be monitored at regular intervals (see section "Adverse reactions").
Excipients. The drug contains lactose, so patients with congenital galactose intolerance, glucose-galactose malabsorption syndrome, Lapp lactase deficiency should not use it.
Use during pregnancy or breastfeeding
Women of reproductive age
During treatment, women of reproductive age should use appropriate contraceptive measures (see section "Contraindications").
Pregnancy
There are no or limited amount of data from the use of ivabradine in pregnant women. Animal studies have shown reproductive toxicity, embryotoxicity and teratogenicity. The potential risk to humans is unknown. Therefore, the use of ivabradine during pregnancy is contraindicated (see section 4.3). Breast-feeding
Animal studies have shown that ivabradine passes into breast milk. Therefore, the use of ivabradine during breastfeeding is contraindicated.
Women who require treatment with ivabradine should discontinue breastfeeding and choose another method of feeding their child.
Fertility
In animal studies, no effect of ivabradine on female or male fertility was detected.
Ability to influence reaction speed when driving vehicles or other mechanisms
A special study to assess the possible effect of ivabradine on the ability to drive was conducted in healthy volunteers and did not reveal any changes in the ability to drive. However, in post-marketing experience, cases of impaired driving due to the occurrence of visual phenomena have been reported. The use of ivabradine may cause temporary visual phenomena, mainly in the form of phosphenes (see section "Adverse reactions"). The possible occurrence of such light phenomena should be taken into account when driving a car or operating machinery in situations where sudden fluctuations in light intensity are possible, especially when driving at night.
Ivabradine has no or negligible influence on the ability to drive and use machines.
Method of administration and doses
The drug Bravadin® is prescribed to adults.
Tablets should be taken orally 2 times a day: in the morning and in the evening during meals (see the "Pharmacokinetics" section).
The Bravadin® 5 mg tablet can be divided into equal doses.
The Bravadin® 7.5 mg tablet cannot be divided.
Symptomatic treatment of chronic stable angina pectoris
It is recommended that decisions regarding initiation of treatment or dose titration be made based on serial heart rate, ECG, or 24-hour outpatient monitoring.
For patients under 75 years of age, the initial dose of ivabradine should not exceed 5 mg twice daily. If patients taking ivabradine 2.5 mg or 5 mg twice daily continue to have symptoms of stable angina after 3–4 weeks of treatment, the dose of ivabradine may be increased to the following dose, provided that the initial dose is well tolerated and the resting heart rate remains > 60 beats/min. The maintenance dose should not exceed 7.5 mg twice daily.
If there is no improvement in angina symptoms within 3 months after starting treatment, ivabradine should be discontinued.
If during treatment the heart rate decreases to < 50 beats/min at rest or the patient develops symptoms of bradycardia (dizziness, weakness, hypotension), the dose should be gradually reduced, including the possibility of using the lowest dose of 2.5 mg 2 times a day (1/2 tablet of Bravadin® 5 mg 2 times a day). After reducing the dose, the heart rate should be monitored (see section "Special instructions"). The drug should be discontinued if the heart rate remains < 50 beats/min or if symptoms of bradycardia persist despite dose reduction.
Treatment of chronic heart failure
Treatment should only be initiated in patients with stable HF upon the recommendation of a physician experienced in the treatment of HF.
The recommended initial dose of ivabradine is 5 mg twice daily. After a two-week course of treatment, the dose can be increased to 7.5 mg twice daily if the heart rate remains > 60 beats/min at rest during ivabradine treatment; or the dose should be reduced to 2.5 mg twice daily (½ tablet of Bravadin® 5 mg twice daily) if the heart rate remains < 50 beats/min at rest or the patient develops symptoms of bradycardia (dizziness, weakness, hypotension). If the heart rate is in the range of 50–60 beats/min, the dose of ivabradine 5 mg twice daily should be left unchanged.
If during treatment the heart rate decreases to < 50 beats/min at rest or the patient develops symptoms of bradycardia, the dose should be gradually reduced to the next lower dose when using ivabradine 7.5 or 5 mg twice daily. If the heart rate is consistently > 60 beats/min at rest, patients taking ivabradine 2.5 or 5 mg twice daily should be gradually increased to the next higher dose.
The drug should be discontinued if during treatment the heart rate remains < 50 beats/min or symptoms of bradycardia persist (see section "Special instructions").
Special patient groups
Elderly patients
For patients over 75 years of age, treatment should be started with a lower initial dose (2.5 mg 2 times a day, i.e. ½ tablet of Bravadin® 5 mg 2 times a day). If further reduction of heart rate is required, the dose can be gradually increased.
Patients with renal insufficiency
Patients with creatinine clearance > 15 ml/min do not require dose adjustment (see section 5.2). Due to the lack of sufficient data, ivabradine should be administered with caution to patients with creatinine clearance < 15 ml/min.
Patients with hepatic insufficiency
Patients with mild hepatic impairment do not require dose adjustment. Ivabradine should be administered with caution to patients with moderate hepatic impairment. Ivabradine is contraindicated in patients with severe hepatic impairment due to the lack of studies in this patient group and the potential for significant increases in blood concentrations (see sections 5.2 and 5.3).
Children.
The safety and efficacy of ivabradine in children (< 18 years) have not been established.
Data on the treatment of chronic heart failure, as described in the sections "Pharmacodynamics" and "Pharmacokinetics", are insufficient to make a dosage recommendation. There are no data on the symptomatic treatment of chronic stable angina.
Overdose
Overdose with ivabradine may lead to severe and prolonged bradycardia (see section 4.8). Severe forms of bradycardia require symptomatic treatment in specialized facilities. In case of bradycardia with impaired hemodynamic parameters, the use of intravenous beta-stimulating agents, such as isoprenaline, is recommended. In extremely severe cases, temporary use of an electrocardiogram (ECG) may be considered.
Side effects
The most common adverse reactions of ivabradine – visual phenomena (phosphenes) (14.5%) and bradycardia (3.3%) – are dose-dependent and due to its pharmacological mechanism of action.
During treatment with the drug, the following adverse reactions may occur, which are distributed 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 determined from the available information).
Blood and lymphatic system disorders: Uncommon: eosinophilia.
Metabolism and metabolism: Uncommon: increased uric acid levels in blood plasma.
Nev
