Coraxan, 56 pcs., 7.5 mg, film-coated tablets

Pharmacological properties of the drug Coraxan

Ivabradine is a cardiac drug that opens a new pharmacotherapeutic class. Ivabradine has an effect solely on heart rate. Ivabradine acts by selectively and specifically inhibiting sinus node f channels, controlling spontaneous diastolic depolarization of the sinus node and reducing heart rate. Ivabradine acts only at the level of the sinus node and does not affect intraatrial, atrioventricular and intraventricular conduction, myocardial contractility and ventricular repolarization. Ivabradine does not change the QT -corrected index. Ivabradine can also interact with retinal h-channels, which are structurally similar to the f-channels of the sinus node of the heart. This can lead to temporary impairment of light perception due to a decrease in the retinal response to bright light stimuli. Trigger factors (sharp changes in lighting), partial inhibition of h-channels determine the possibility of developing photopsia (unwanted transient visual impairment in a limited area of ​​the visual field). The main pharmacodynamic feature of ivabradine in humans is a selective reduction exclusively in heart rate. When using the usual recommended dose (5 or 7.5 mg 2 times a day), there is a decrease in heart rate by approximately 10–15 beats/min (depending on the initial heart rate) at rest and during exercise. This reduces the work of the heart and reduces oxygen consumption by the myocardium. The antianginal and anti-ischemic effectiveness of Coraxan has been proven in four randomized, blind, placebo-controlled studies (2 compared with placebo and 1 each with atenolol and amlodipine). These studies included 3222 patients with stable angina, of whom 2168 received ivabradine. Already after 3–4 weeks of treatment with ivabradine at a dose of 5 mg 2 times a day, its effectiveness was proven (according to physical stress tests). Additional benefits of ivabradine at a dose of 7.5 mg 2 times a day were proven in a controlled comparative study with atenolol. After 1 month of treatment with ivabradine at a dose of 5 mg 2 times a day, the duration of the exercise test in the interdose period increased by 1 minute. The dose of ivabradine was increased to 7.5 mg 2 times a day, and after 3 months of use, a further increase in the duration of the load by approximately 25 s was noted. In this study, the antianginal and anti-ischemic benefits of ivabradine were confirmed in patients aged 65 years and older. The effectiveness of ivabradine in doses of 5 and 7.5 mg 2 times a day was constant in all studies in all parameters (total duration of exercise, time to the development of an angina attack, time to the development of ST by 1 mm) and was accompanied by a decrease in the number of attacks of stable angina pectoris by approximately 70%. The dosing regimen of ivabradine 2 times a day provided a stable effective effect for 24 hours. The effectiveness of ivabradine was confirmed in studies that lasted 3–4 months. During treatment, there were no cases of pharmacological tolerance (loss of effectiveness) or withdrawal effects after sudden cessation of treatment. The antianginal and anti-ischemic effects of ivabradine were accompanied by a dose-dependent decrease in heart rate and a possible decrease in double product (DP) at rest and during exercise (DP is an indicator reflecting the myocardial oxygen demand, DP = heart rate • systolic blood pressure). The effect of ivabradine on blood pressure and peripheral vascular resistance was minimal and not clinically significant. A 1-year study of ivabradine in 713 patients confirmed a reduction in heart rate and demonstrated no effect of ivabradine on glucose and lipid metabolism. Studies have proven the anti-ischemic and antianginal effectiveness of ivabradine in patients with diabetes mellitus. The safety profile of ivabradine in this population did not differ from the safety profile in the general population. Clinical studies have proven the antianginal effectiveness of ivabradine, due to a selective decrease in heart rate in the absence of a negative effect on myocardial contractility and conductivity. The 4-month ASSOCIATE study involving 880 patients with angina pectoris demonstrated additional anti-ischemic efficacy of ivabradine when administered together with a beta-adrenergic blocker (atenolol 50 mg). According to the treadmill test, the increase in the total duration of physical activity during treatment with ivabradine and a β-adrenergic receptor blocker was 3 times higher than the result obtained using a β-adrenergic blocker alone. The use of ivabradine together with a β-adrenergic receptor blocker significantly improves stress test parameters and is safe in patients with coronary artery disease. In the double-blind, placebo-controlled BEAUTIFUL trial involving 10,917 patients with coronary artery disease and left ventricular dysfunction, treatment with ivabradine, given in addition to optimal preventive treatment (acetylsalicylic acid, beta-blocker, statin, ACE inhibitor) reduced the risk of myocardial infarction by 36 % and the need for revascularization by 30% in patients with coronary artery disease and heart rate 70 beats/min. High clinical efficacy and tolerability make the use of ivabradine particularly advisable in patients with restrictions or contraindications to the use of beta-blockers or for co-administration with beta-adrenergic blockers. After oral administration, ivabradine is rapidly released and dissolves well (10 mg/ml). Ivabradine is rapidly and almost completely absorbed. The maximum plasma concentration is reached after approximately 1 hour. The bioavailability of ivabradine is approximately 40%. Eating food does not affect the rate of absorption and concentration of ivabradine. Approximately 70% of ivabradine is bound to plasma proteins. The maximum plasma concentration with long-term use of the drug at the recommended initial dose of 5 mg 2 times a day is approximately 22 ng/ml. The average concentration in blood plasma at the stable concentration stage is 10 ng/ml. Ivabradine is extensively metabolized in the liver and intestines by oxidation by the cytochrome P450 3A4 (CYP 3A4) system. The main active metabolite of ivabradine is its N-desmethylated derivative (S18 982), its concentration is 40% that of ivabradine hydrochloride, and it has the same pharmacokinetic and pharmacodynamic properties. The main active metabolite is also metabolized by the CYP3A4 cytochrome system. Ivabradine has low affinity for CYP 3A4 and does not activate or inhibit it, thus it will not significantly alter the metabolism of CYP 3A4 or its plasma concentration. Conversely, CYP3A4 inhibitors and stimulants may significantly affect the plasma concentrations of ivabradine. The half-life of ivabradine is 2 hours, the effective half-life is 11 hours. The total clearance of ivabradine is 400 ml/min. Renal clearance of ivabradine is 70 ml/min. Excretion of metabolites and a small amount of unchanged active substance occurs equally in urine and feces. Approximately 4% of the active substance is excreted unchanged in the urine. The kinetics of ivabradine for doses of 0.5–24 mg is linear. Analysis of the pharmacokinetics/pharmacodynamics ratio demonstrated a linear dependence of the decrease in heart rate on the increase in the concentration of ivabradine and its active metabolite in the blood plasma for doses of 15–20 mg. High plasma concentrations of ivabradine may be due to its use in combination with strong CYP3A4 inhibitors, which can lead to a significant decrease in heart rate; the risk is reduced when used with moderate CYP3A4 inhibitors.

Instructions for use CORAXAN®

Mechanism of action

Ivabradine consists of selective and specific inhibition of If channels of the sinus node, which leads to prolongation of spontaneous diastolic depolarization and a dose-dependent decrease in heart rate. Ivabradine does not affect intraatrial, atrioventricular or intraventricular conduction time, myocardial contractility, or ventricular repolarization.

Ivabradine is also able to interact with the Ih channels of the retina, similar to the If channels of the heart, which are involved in causing temporary changes in the visual perception system by changing the retinal response to bright light stimuli. Under certain conditions (eg, rapid changes in light), ivabradine partially inhibits the electrical impulse Ih, which sometimes leads to light sensations in some patients. These light sensations (phosphenes) are described as a brief sensation of increased brightness in a limited part of the visual field.

Pharmacodynamic effects

The main pharmacodynamic property of ivabradine in humans is a specific, dose-dependent decrease in heart rate. Analysis of the decrease in heart rate at doses exceeding 20 mg 2 times / day indicates a tendency towards a plateau effect, which reduces the risk of severe bradycardia (less than 40 beats / min).

At the usually recommended dose, the decrease in heart rate at rest and during exercise is approximately 10 beats/min. This leads to a decrease in the load on the heart and oxygen consumption by the myocardium. Ivabradine does not affect either intracardiac conduction, contractility (without negative inotropic effects), or ventricular repolarization:

• clinical electrophysiological studies have shown that ivabradine does not affect either AV and intraatrial conduction times or the QT interval;
• in patients with left ventricular dysfunction (left ventricular ejection fraction, LVEF, 30 to 45%), ivabradine did not adversely affect LVEF.

Clinical efficacy and safety

The antianginal and anti-ischemic effects of ivabradine were studied in 5 double-blind randomized studies (3 placebo-controlled studies, 1 comparative study with atenolol and 1 comparative study with amlodipine). A total of 4111 patients with stable angina participated in these studies, 2617 of whom received ivabradine.

It was shown that ivabradine at a dose of 5 mg 2 times / day had a beneficial effect on all indicators of exercise tests over 3-4 weeks of therapy. Efficacy was also confirmed for a dose of 7.5 mg 2 times a day. In particular, in a comparative study with atenolol, an additional advantage over a dose of 5 mg 2 times / day was established:

• At the lowest activity of the drug, the total duration of physical activity increased by approximately 1 minute after one month of dosing at a dose of 5 mg 2 times / day, a subsequent increase in duration by almost 25 seconds occurred after an additional three-month period with forced titration to 7.5 mg 2 times / day. This study confirmed the antianginal and anti-ischemic efficacy of ivabradine in patients aged 65 years and older. The effectiveness of ivabradine at doses of 5 mg and 7.5 mg 2 times a day was observed throughout all studies according to exercise testing parameters (total duration of physical activity, time to onset of limited angina, time to onset of angina, and time to development of ST segment depression by 1 mm), and was also accompanied by a decrease in the incidence of angina attacks by approximately 70%. When taking ivabradine 2 times a day, uniform effectiveness of action is ensured over 24 hours.

In a randomized, placebo-controlled study involving 889 patients, ivabradine taken in combination with atenolol 50 mg 1 time/day showed an additional effect on exercise tolerance test parameters at minimal drug activity (12 hours after oral administration).

A randomized, placebo-controlled trial involving 725 patients found no additional efficacy of ivabradine compared with amlodipine at the lowest drug activity (12 hours after oral dosing), while additional efficacy was shown at peak drug activity (3-4 hours after oral dosing). hours after oral dosing).

In a randomized, placebo-controlled trial involving 1,277 patients, ivabradine demonstrated statistically significant incremental efficacy in treatment response (defined as a reduction in at least 3 angina attacks per week and/or an increase in ST-segment depression time of at least 1 mm). , for 60 s during the treadmill test) while taking amlodipine 5 mg/day or nifedipine GITS 30 mg/day (after 12 hours of oral ivabradine) after a 6-week treatment period (OR=1.3, 95% CI [1.0- 1.7]; p=0.012). Ivabradine did not show additional efficacy on secondary endpoints of EET parameters during the entire period of drug action, while at the peak (3-4 hours after oral administration of ivabradine) additional efficacy was demonstrated.

In studies of the clinical effectiveness of the drug, the effects of ivabradine were fully maintained over 3- and 4-month courses of treatment. During treatment, there were no signs of the development of pharmacological tolerance (loss of effectiveness), and after sudden cessation of treatment, no withdrawal syndrome was observed. The antianginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as a significant decrease in the so-called double product (heart rate x systolic blood pressure), both at rest and during exercise. The effect on blood pressure and peripheral vascular resistance was negligible and not clinically significant.

A prolonged reduction in heart rate was shown in patients who received ivabradine for at least 1 year (n=713). No effects on glucose or fat metabolism were observed.

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

The BEAUTIFUL trial was a large study involving 10,917 patients with coronary artery disease and left ventricular dysfunction (LVEF <40%) receiving optimal initial therapy, which included beta-blockers in 86.9% of patients. The primary outcome measure was a composite of cardiovascular mortality, hospitalization for acute myocardial infarction, hospitalization for a new event, or worsening heart failure. The study showed no difference in achievement of the primary composite criterion in the ivabradine group and in the placebo group (relative risk ivabradine/placebo 1.00, p=0.945).

In a post hoc analysis of the subgroup of patients with symptomatic angina at randomization (n=1507), there were no safety signals for cardiovascular mortality, hospitalization for acute myocardial infarction or heart failure (ivabradine 12.0% vs placebo 15.5%, p= 0.05).

The large SIGNIFY trial was conducted in 19,102 patients with coronary artery disease and without clinical heart failure (LVEF >40%) receiving optimal background therapy. Therapeutic regimen using more than the approved dose (initial dose 7.5 mg 2 times / day (5 mg 2 times / day if age ≥75 years) and titrated to 10 mg 2 times / day). The primary outcome was a composite of cardiovascular mortality and nonfatal myocardial infarction. The study showed no difference in the primary composite endpoint (PCE) in the ivabradine group compared with the placebo group (ivabradine/placebo relative risk 1.08, p=0.197). Bradycardia was reported in 17.9% of patients in the ivabradine group (2.1% in the placebo group). 7.1% of patients in the study received verapamil, diltiazem, or strong CYP3A4 inhibitors. A small statistically significant increase in RSE was found in a prespecified subgroup of patients with CCS class II or higher angina at baseline (n=12,049) (annual incidence 3.4% vs 2.9%, relative risk ivabradine/placebo 1.18, p=0.018), but not in the subgroup of general angina with class ≥ I (n=14,286) (relative risk of ivabradine/placebo 1.11, p=0.110).

The use of a dose higher than approved in the study does not fully explain these results.

SHIFT was a large multicenter, international, randomized, double-blind, placebo-controlled trial involving 6505 adult patients with stable chronic heart failure (for ≥4 weeks).

The study included a population of patients with heart failure class II-IV according to the NYHA classification, with reduced left ventricular ejection fraction (LVEF≤35%) and with a heart rate ≥70 beats/min. Patients received standard treatment, including beta-blockers (89%), ACE inhibitors and/or angiotensin II antagonists (91%), diuretics (83%), and antialdosterone drugs (60%). In the ivabradine group, 67% of patients were treated with 7.5 mg 2 times a day. The average follow-up duration of treatment was 22.9 months.

Treatment with ivabradine was associated with a decrease in heart rate by an average of 15 beats/min from a baseline value of 80 beats/min. The difference in heart rate between ivabradine and placebo was 10.8 beats/min at day 28, 9.8 beats/min at month 12, and 8.3 beats/min at month 24.

The study showed a clinically and statistically significant 18% risk reduction relative to the primary composite endpoint of cardiovascular mortality and hospitalization for worsening heart failure (relative risk:

• 0.82, 95% CI [0.75%;
• 0.90], p<0.0001), which was evident after 3 months of treatment after initiation of therapy. The absolute risk reduction was 4.2%. The outcome for the primary endpoint was primarily dependent on the endpoint of heart failure, hospitalization for worsening heart failure (4.7% absolute risk reduction) and heart failure mortality (1.1% absolute risk reduction).

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

The reduction at the primary endpoint was observed equally regardless of gender, NYHA functional class, ischemic or non-ischemic etiology of heart failure, or a history of diabetes mellitus or hypertension.

In the subgroup of patients with heart rate >75 beats/min (n=4150), there was a greater reduction in the primary composite point by 24% (relative risk:

• 0.76, 95% CI [0.68;
• 0.85], p<0.0001) and other secondary endpoints, including all-cause mortality (relative risk: 0.83, 95% CI [0.72;
• 0.96], p=0.0109) and cardiovascular death (relative risk: 0.83, 95% CI [0.71;
• 0.97], p=0.0166). In this subgroup of patients, the safety profile of ivabradine was consistent with that in other populations.

There was a significant improvement in the primary composite endpoint in all groups of patients receiving beta-blockers (relative risk:

• 0.85, 95% CI [0.76;
• 0.94]). In the subgroup of patients with heart rate >75 beats/min and on recommended target doses of beta-blockers, there was no statistically significant benefit on the primary endpoint (relative risk: 0.97, 95% CI [0.74;
• 1.28]) and other secondary endpoints, including hospitalization due to worsening heart failure (relative risk: 0.79, 95% CI [0.56;
• 1.10]) or death from heart failure (relative risk: 0.69, 95% CI [0.31;
• 1.53]).

There was a significant improvement in recent NYHA functional class in 887 (28%) patients receiving ivabradine compared with 776 (24%) patients receiving placebo (p=0.001).

In a randomized, placebo-controlled trial of 97 patients, specific ophthalmic tests were performed to document the function of the cone and rod systems and afferent visual pathways (i.e., electroretinogram, static and kinetic visual fields, color vision, visual acuity) . In patients taking ivabradine for the treatment of chronic stable angina for more than 3 years, ivabradine did not show retinal toxicity.

Pediatric population

A randomized, double-blind, placebo-controlled study was conducted in 116 pediatric patients with chronic heart failure and dilated cardiomyopathy (DCM) (17 aged 6-12 months, 36 aged 1-3 years, and 63 aged 3-18 years). ). 74 patients received ivabradine (ratio 2:

• 1) in addition to optimal basic therapy.

The initial dose was 0.02 mg/kg 2 times/day in the age subgroup 6-12 months, 0.05 mg/kg 2 times/day in the age subgroup 1-3 years and 3-18 years less than 40 kg, as well as 2.5 mg 2 times/day. days in the age subgroup 3-18 years and ≥40 kg. The dose was adapted depending on the therapeutic response with maximum doses of 0.2 mg/kg 2 times/day, 0.3 mg/kg 2 times/day and 15 mg 2 times/day, respectively. In this study, ivabradine was administered orally in liquid or tablet form twice daily. The absence of a pharmacokinetic difference between the two forms was demonstrated in an open-label, randomized, two-period crossover study in 24 healthy adult volunteers.

During the titration period of 2 to 8 weeks, a 20% reduction in heart rate without bradycardia was achieved in 69.9% of patients in the ivabradine group, compared with 12.2% in the placebo group (Odds ratio:

• E=17.24;
• CI 95% [5.91;
• 50.30]).

The average doses of ivabradine to achieve a 20% reduction in heart rate were 0.13±0.04 mg/kg 2 times/day, 0.10±0.04 mg/kg 2 times/day and 4.1±2.2 mg 2 times/day for age subpopulations 1-3 years, 3-18 years with body weight less than 40 kg, 3-18 years and with body weight ≥40 kg, respectively.

After 12 months of observation, the mean left ventricular ejection fraction increased from 31.8% to 45.3% in the ivabradine group compared with dynamics from 35.4% to 42.3% in the placebo group. There was an improvement in NYHA class in 37.7% of patients in the ivabradine group compared with 25.0% of patients in the placebo group. The differences were not statistically significant.

The safety profile at one year of follow-up was similar to that described in adult patients with congestive heart failure.

The long-term effects of ivabradine on growth, puberty and overall development, as well as the long-term effectiveness of ivabradine therapy in childhood to reduce cardiovascular morbidity and mortality have not been studied.

The European Medicines Agency does not require mandatory submission of results from studies of Coraxan® in the treatment of angina in all subpopulations of pediatric populations.

The European Medicines Agency has postponed the mandatory submission of results from studies of Coraxan® in the treatment of chronic heart failure in children aged 0 to 6 months.

Use of the drug Coraxan

Orally. Prescribed for adults 2 times a day, morning and evening during meals. Coraxan 5 mg tablet can be divided; 7.5 mg tablets are not split. The recommended starting dose of ivabradine is 5 mg 2 times a day (1 tablet of Coraxan 5 mg 2 times a day). After 3–4 weeks of treatment, if further reduction in heart rate is necessary, the dose can be increased to 7.5 mg 2 times a day (1 tablet of Coraxan 7.5 mg 2 times a day). If during the treatment period the heart rate becomes less than 50 beats/min or the patient experiences symptoms resulting from bradycardia, it is necessary to reduce the dose of the drug by titration, including the possibility of using ivabradine at a dose of 2.5 mg 2 times a day (1/2 t of Coraxan tablets 5 mg 2 times a day). The maximum recommended therapeutic daily dose of ivabradine is 15 mg. If the heart rate remains less than 50 beats per minute, stop using the drug. The use of Coraxan 5 mg in elderly patients, patients with heart failure, mild to moderate chronic renal and liver failure, diabetes mellitus, and asthma does not require dose adjustment.

Coraxan, 56 pcs., 7.5 mg, film-coated tablets

Ivabradine is a drug that slows the heart rate, the mechanism of action of which is the selective and specific inhibition of I

f sinus node channels that control spontaneous diastolic depolarization in the sinus node and regulate heart rate (HR). Ivabradine has a selective effect on the sinus node, without affecting the timing of impulses along the intra-atrial, atrioventricular and intraventricular pathways, as well as on myocardial contractility and ventricular repolarization.

Ivabradine may also interact with I

h channels of the retina, similar to
the I
f channels of the heart, involved in the occurrence of temporary changes in the visual perception system due to changes in the retinal reaction to bright light stimuli.

Under provoking circumstances (for example, a rapid change in brightness in the visual field), partial inhibition of I

h channels with ivabradine causes
the phenomenon of changes in light perception (photopsia)
. Photopsia is characterized by a transient change in brightness in a limited area of ​​the visual field (see section “Side effects”).

The main pharmacological feature of ivabradine is the ability of a dose-dependent decrease (HR). An analysis of the dependence of the magnitude of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg twice a day and revealed a tendency to achieve a “plateau” effect (no increase in the therapeutic effect with a further increase in dose), which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min) (see section “Side effects”).

When the drug is prescribed in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10–15 beats/min at rest and during physical activity. As a result, the work of the heart decreases and the myocardium’s need for oxygen decreases.

Ivabradine does not affect intracardiac conduction, myocardial contractility (does not cause a negative inotropic effect) and the process of repolarization of the ventricles of the heart. In clinical electrophysiological studies, ivabradine had no effect on the timing of impulses along the atrioventricular or intraventricular pathways, as well as on corrected QT intervals. In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30–45%), ivabradine has been shown to have no effect on myocardial contractility.

It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of stress tests after 3–4 weeks of therapy. Efficacy was also confirmed for a dose of 7.5 mg 2 times a day. In particular, an additional effect when increasing the dose from 5 to 7.5 mg 2 times a day was established in a comparative study with atenolol. The time spent performing physical activity increased by approximately 1 minute after 1 month of using ivabradine at a dose of 5 mg 2 times a day, while after an additional 3-month course of taking ivabradine at a dose of 7.5 mg 2 times a day orally, a further increase in this indicator was noted for 25 seconds. The antianginal and anti-ischemic activity of ivabradine was also confirmed in patients aged 65 years and older. The effectiveness of ivabradine when used in doses of 5 mg and 7.5 mg 2 times a day was observed in relation to all indicators of stress tests (total duration of physical activity, time to a limiting attack of angina, time to the onset of an attack of angina and time to the development of ST segment depression at 1 mm), and was also accompanied by a decrease in the incidence of angina attacks by approximately 70%. The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours.

In patients taking ivabradine, additional effectiveness of ivabradine was shown in relation to all indicators of stress tests when added to the maximum dose of atenolol (50 mg) at the decline of therapeutic activity (12 hours after oral administration).

There is no improvement in the effectiveness of ivabradine when added to the maximum dose of amlodipine at the decline in therapeutic activity (12 hours after oral administration), while at the maximum of activity (3-4 hours after oral administration), additional effectiveness of ivabradine has been proven.

In clinical efficacy studies of the drug, the effects of ivabradine were fully maintained over the 3- and 4-month treatment periods. During treatment, there were no signs of the development of tolerance (decreased effectiveness), and after cessation of treatment, no withdrawal syndrome was observed. The antianginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as a significant decrease in the work product (heart rate × systolic blood pressure), both at rest and during exercise. The effect on blood pressure (BP) and total peripheral vascular resistance (TPVR) was minor and clinically insignificant.

A sustained decrease in heart rate was observed in patients taking ivabradine for at least 1 year. No effect on carbohydrate metabolism and lipid profile was observed.

In patients with diabetes mellitus, the efficacy and safety of ivabradine were similar to those in the general patient population.

In a study of patients with coronary artery disease without clinical manifestations of heart failure (LVEF more than 40%) during maintenance therapy, treatment with ivabradine at doses higher than recommended (initial dose 7.5 mg twice daily (5 mg twice daily for older patients) 75 years), which was then titrated to 10 mg twice daily) had no significant effect on the primary composite endpoint (death from a cardiovascular cause or development of nonfatal myocardial infarction). The incidence of bradycardia in the group of patients receiving ivabradine was 17.9%. 7.1% of patients in the study took verapamil, diltiazem, or strong CYP3A4 inhibitors.

In patients with Canadian Cardiological Society class II or higher angina, there was a small statistically significant increase in the incidence of the primary composite endpoint with ivabradine, which was not observed in the subgroup of all patients with angina (class I or higher).

In a study of patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers, there were no differences between the groups of patients taking ivabradine against the background of standard therapy and placebo in the total incidence of fatal outcomes from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening symptoms of chronic heart failure (CHF). In patients with symptomatic angina, there was no significant difference in the incidence of death due to a cardiovascular cause or hospitalization due to nonfatal myocardial infarction or heart failure (incidence of 12.0% in the ivabradine group and 15.5% in the placebo group, respectively). . The use of ivabradine in patients with a heart rate of at least 70 beats/min showed a reduction in the frequency of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the frequency of revascularization by 30%.

In patients with angina pectoris while taking ivabradine, there was a reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or increased symptoms of CHF) by 24%. The noted therapeutic benefit is achieved primarily by reducing the frequency of hospitalization for acute myocardial infarction by 42%.

The reduction in the incidence of hospitalization for fatal and non-fatal myocardial infarction in patients with heart rate more than 70 beats/min is even more significant and reaches 73%. In general, the drug was well tolerated and safe.

The use of ivabradine in patients with CHF II-IV functional class according to the NYHA classification with LVEF less than 35% showed a clinically and statistically significant reduction in the relative risk of complications (the frequency of deaths from cardiovascular diseases and a decrease in the number of hospitalizations due to increased symptoms of the disease). CHF) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months from the start of therapy.

A decrease in mortality from cardiovascular diseases and a decrease in the number of hospitalizations due to increased symptoms of CHF was observed regardless of age, gender, functional class of CHF, the use of beta-blockers, ischemic or non-ischemic etiology of CHF, the presence of diabetes mellitus or a history of arterial hypertension.

Patients with symptoms of CHF in sinus rhythm and with a heart rate of at least 70 beats/min received standard therapy, including the use of beta-blockers (89%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists (91%), diuretics (83%). and aldosterone antagonists (60%).

It has been shown that use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug.

The use of ivabradine showed an improvement in the functional class of CHF according to the NYHA classification.

In patients with a heart rate of 80 beats/min, a decrease in heart rate by an average of 15 beats/min was noted.

Contraindications to the use of the drug Coraxan

Hypersensitivity to ivabradine or other components of the drug; bradycardia (heart rate at rest less than 60 beats/min); cardiogenic shock; severe liver failure; sick sinus syndrome; sinoatrial block; the patient has an artificial pacemaker; AV block of the third degree; combination with strong and moderate CYP 3A4 inhibitors (antifungal drugs - azole derivatives (ketoconazole, etc.), macrolide antibiotics (clarithromycin, erythromycin for oral use, josamycin, telithromycin), antiviral drugs (nelfinavir, ritonavir and nefazodone); pregnancy and breastfeeding; acute myocardial infarction and unstable angina (due to lack of clinical data); severe hypotension - blood pressure less than 90/50 mmHg (due to insufficient clinical data); heart failure of functional classes III-IV according to NYHA (due to lack of clinical data).

Side effects of the drug Coraxan

Side effects of ivabradine are dose-dependent and due to its pharmacological mechanism of action. Visual impairment (1/10)

Photopsia (light flashes appearing before the eyes - increased brightness in the visual field) are observed in approximately 14.5% of patients and are transient in nature. Photopsia are usually initiated by sudden changes in light intensity and occur during the first 2 months of treatment. Typically, photopsia is mild or moderate and resolves spontaneously during treatment in 77.5% of patients or upon cessation of treatment. In less than 1% of patients, the development of ophthalmological symptoms requires discontinuation of treatment. Blurred vision (1/100, ≤1/10). From the cardiovascular system (1/100, ≤1/10)

• Bradycardia . In 3.3% of patients, bradycardia may occur in the first 2–3 months of treatment. 0.5% of patients have a severe form of bradycardia (heart rate less than 40 beats/min);
• AV block of the first degree;
• Ventricular extrasystole. Very rarely (1/1000, ≤ 1/100) increased heart rate and supraventricular extrasystole may occur.

From the gastrointestinal tract Rarely (1/1000, ≤1/100), nausea, constipation or diarrhea may occur. From the side of the central nervous system : Possible occurrence (1/100, ≤1/10) of headache (in the first months of use), dizziness (reliably associated with bradycardia). Laboratory parameters rarely (1/1000, ≤1/100) may increase the level of creatinine and uric acid in the blood plasma, eosinophilia. Other manifestations (1/1000, ≤ 1/100) - convulsions, dyspnea.

Special instructions for the use of the drug Coraxan

Patients with diabetes mellitus and asthma should adhere to the same recommendations regarding route of administration and dosage as other patients. Taking into account the limited number of patients aged 75 years and older who took part in studies of ivabradine, treatment of such patients begins with a dose of 2.5 mg (1/2 t of Coraxan 5 mg tablets) 2 times a day. If it is necessary to further reduce heart rate, the dose can be increased by titration. Ivabradine should not be prescribed to prevent or treat arrhythmias. If a patient experiences tachyarrhythmia (ventricular or supraventricular) during treatment with ivabradine, treatment with ivabradine is not advisable. Ivabradine is not recommended for use in patients with atrial fibrillation and other types of arrhythmias that impair sinus node function. When treating with ivabradine, it is necessary to regularly monitor the patient’s condition in order to exclude the possibility of developing atrial fibrillation (paroxysmal or permanent) and, if necessary, conduct an ECG study. Ivabradine is not recommended for patients with second degree AV block. It is not recommended to prescribe ivabradine to patients with a heart rate ≤60 beats/min at rest. If during treatment the heart rate becomes less than 50 beats/min or the patient experiences symptoms that are a consequence of bradycardia (dizziness, weakness, hypotension), it is necessary to reduce the dose by titration, including the possibility of using ivabradine at a dose of 2.5 mg (1/2 t tablet drug Coraxan 5 mg) 2 times a day. If the heart rate remains below 50 beats/min, the use of ivabradine should be discontinued. A study in patients with heart failure (left ventricular ejection fraction 30–45%) demonstrated that ivabradine did not have a negative effect on ejection fraction in these patients. Use with caution in patients with asymptomatic left ventricular dysfunction and in patients with NYHA functional class II heart failure (due to the lack of sufficient data). The mechanism of action of ivabradine determines its effect on retinal function. To date, there is no data regarding the toxic effect of ivabradine on the retina when ivabradine is used for a year. There are no data regarding longer-term use of ivabradine at this time. If unexpected (see SIDE EFFECTS) retinal abnormalities occur, treatment should be discontinued. Use with caution in patients with retinitis pigmentosa. Ivabradine is not recommended for use in patients immediately after a stroke (due to the lack of clinical data). Ivabradine is not recommended for use in children and adolescents, as studies have not been conducted in this group of patients. The drug contains lactose, so it should not be prescribed to patients with congenital galactose intolerance, glucose-galactose malabsorption syndrome, or Lapp lactase deficiency. Ivabradine is not recommended for use with calcium channel blockers that reduce heart rate (verapamil or diltiazem). There are no data regarding the safety of ivabradine in studies of short- and long-acting nitrates and dihydropyridine calcium channel blockers (amlodipine). Ivabradine should be used with caution in patients with mild to moderate hypotension (due to insufficient data). There have been no reports regarding the risk of severe bradycardia during restoration of sinus rhythm following pharmacological cardioversion in patients treated with ivabradine. Despite this, due to the lack of sufficient data, DC cardioversion is not recommended earlier than 24 hours after the last dose of ivabradine. Ivabradine is not recommended for use in patients with congenital long QT and in patients taking drugs that prolong the QT . If it is necessary to prescribe ivabradine to such patients, it is necessary to periodically monitor heart rate and QT . Patients with mild hepatic impairment do not require dose adjustment. Ivabradine should be prescribed with caution to patients with moderately severe liver failure. Patients with a creatinine clearance of 15 ml/min do not require dose adjustment. Ivabradine should be administered with caution to patients with creatinine clearance ≤15 ml/min (due to insufficient data). There has been no negative effect of ivabradine on the ability to drive vehicles or operate machinery, however, the use of ivabradine may cause transient visual impairment (the appearance of flashes of light in front of the eyes or blurred vision), which is usually initiated by sudden changes in light intensity. This must be taken into account when driving vehicles and operating machinery. There is no drug withdrawal syndrome observed.

Coraxan®

Ivabradine is a drug that slows the heart rate, the mechanism of action of which is to selectively and specifically inhibit the If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate (HR).

Ivabradine has a selective effect on the sinus node, without affecting the timing of impulses along the intra-atrial, atrioventricular and intraventricular pathways, as well as on myocardial contractility and ventricular repolarization.

Ivabradine may also interact with the Ih channels of the retina, similar to the If channels of the heart, which are involved in causing temporary changes in the visual perception system by changing the retinal response to bright light stimuli.

Under provoking circumstances (for example, a rapid change in brightness in the visual field), partial inhibition of Ih channels by ivabradine causes the phenomenon of changes in light perception (photopsia). Photopsia is characterized by a transient change in brightness in a limited area of ​​the visual field (see section “Side effects”).

The main pharmacological feature of ivabradine is the ability of a dose-dependent decrease (HR). An analysis of the dependence of the magnitude of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg twice a day and revealed a tendency to achieve a “plateau” effect (no increase in the therapeutic effect with a further increase in the dose), which reduces the risk of developing bradycardia (heart rate less than 40 beats/min) (see section “Side effects”).

When the drug is prescribed in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10-15 beats/min at rest and during physical activity. As a result, the work of the heart decreases and the myocardium’s need for oxygen decreases.

Ivabradine does not affect intracardiac conduction, myocardial contractility (does not cause a negative inotropic effect) and the process of repolarization of the ventricles of the heart. In clinical electrophysiological studies, ivabradine had no effect on the timing of impulses along the atrioventricular or intraventricular pathways, as well as on corrected QT intervals.

In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%), ivabradine was shown to have no effect on myocardial contractility.

It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of stress tests after 3-4 weeks of therapy. Efficacy was also confirmed for a dose of 7.5 mg 2 times a day. In particular, an additional effect when increasing the dose from 5 to 7.5 mg 2 times a day was established in a comparative study with atenolol. The time for performing physical activity increased by approximately 1 minute after the 1st month of using ivabradine at a dose of 5 mg 2 times a day, while after an additional 3-month course of taking ivabradine at a dose of 7.5 mg 2 times a day orally, a further increase in this indicator was noted for 25 seconds. The antianginal and anti-ischemic activity of ivabradine was also confirmed in patients aged 65 years and older. The effectiveness of ivabradine when used in doses of 5 mg and 7.5 mg 2 times a day was observed in relation to all indicators of stress tests (total duration of physical activity, time to a limiting attack of angina, time to the onset of an attack of angina and time to the development of ST segment depression at 1 mm), and was also accompanied by a decrease in the incidence of angina attacks by approximately 70%. The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours.

In patients taking ivabradine, additional effectiveness of ivabradine was shown in relation to all indicators of stress tests when added to the maximum dose of atenolol (50 mg) at the decline of therapeutic activity (12 hours after oral administration).

There is no improvement in the effectiveness of ivabradine when added to the maximum dose of amlodipine at the decline in therapeutic activity (12 hours after oral administration), while at the maximum of activity (3-4 hours after oral administration), the additional effectiveness of ivabradine has been proven.

In clinical efficacy studies of the drug, the effects of ivabradine were fully maintained over the 3- and 4-month treatment periods. During treatment, there were no signs of the development of tolerance (decreased effectiveness), and after cessation of treatment, no withdrawal syndrome was observed. The antianginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as a significant decrease in the work product (heart rate x systolic blood pressure), both at rest and during exercise. The effect on blood pressure (BP) and total peripheral vascular resistance (TPVR) was minor and clinically insignificant.

A sustained decrease in heart rate was observed in patients taking ivabradine for at least 1 year. No effect on carbohydrate metabolism and lipid profile was observed.

In patients with diabetes mellitus, the efficacy and safety of ivabradine were similar to those in the general patient population.

In a study of patients with coronary artery disease without clinical manifestations of heart failure (LVEF more than 40%) during maintenance therapy, treatment with ivabradine at doses higher than recommended (initial dose 7.5 mg twice daily (5 mg twice daily for older patients) 75 years), which was then titrated to 10 mg twice daily) had no significant effect on the primary composite endpoint (death from a cardiovascular cause or development of nonfatal myocardial infarction). The incidence of bradycardia in the group of patients receiving ivabradine was 17.9%. 7.1% of patients in the study took verapamil, diltiazem, or strong CYP3A4 inhibitors.

In patients with Canadian Cardiological Society class II or higher angina, there was a small statistically significant increase in the incidence of the primary composite endpoint with ivabradine, which was not observed in the subgroup of all patients with angina (class I or higher).

In a study of patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers, there were no differences between the groups of patients taking ivabradine against the background of standard therapy and placebo in the total incidence of fatal outcomes from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening symptoms of chronic heart failure (CHF).

In patients with symptomatic angina, there was no significant difference in the incidence of death due to a cardiovascular cause or hospitalization due to nonfatal myocardial infarction or heart failure (incidence of 12.0% in the ivabradine group and 15.5% in the placebo group, respectively). ). The use of ivabradine in patients with a heart rate of at least 70 beats/min showed a reduction in the frequency of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the frequency of revascularization by 30%.

In patients with angina pectoris while taking ivabradine, there was a reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or increased symptoms of CHF) by 24%. The noted therapeutic benefit is achieved primarily by reducing the frequency of hospitalization for acute myocardial infarction by 42%.

The reduction in the incidence of hospitalization for fatal and non-fatal myocardial infarction in patients with heart rate more than 70 beats/min is even more significant and reaches 73%. In general, the drug was well tolerated and safe.

The use of ivabradine in patients with CHF II-IV functional class according to the NYHA classification with LVEF less than 35% showed a clinically and statistically significant reduction in the relative risk of complications (the frequency of deaths from cardiovascular diseases and a decrease in the number of hospitalizations due to increased symptoms of the disease). CHF) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months from the start of therapy.

A decrease in mortality from cardiovascular diseases and a decrease in the number of hospitalizations due to increased symptoms of CHF was observed regardless of age, gender, functional class of CHF, the use of beta-blockers, ischemic or non-ischemic etiology of CHF, the presence of diabetes mellitus or a history of arterial hypertension.

Patients with symptoms of CHF in sinus rhythm and with a heart rate of at least 70 beats/min received standard therapy, including the use of beta-blockers (89%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists (91%), diuretics (83%), and aldosterone antagonists (60%).

It has been shown that use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug.

The use of ivabradine showed an improvement in the functional class of CHF according to the NYHA classification.

In patients with a heart rate of 80 beats/min, a decrease in heart rate by an average of 15 beats/min was noted.

Interactions of the drug Coraxan

Pharmacodynamic interactions Ivabradine is not recommended for use in combination with drugs that prolong the QT interval, namely:

• cardiac drugs (quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone);
• other drugs that prolong the QT (pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin IV).

Prolongation of the QT resulting from the use of the above drugs may increase due to a decrease in heart rate. Should be used with caution. Pharmacokinetic interactions Inhibitors or stimulators of cytochrome P450 3A4 (CYP 3A4). Not recommended for use in combination with moderate CYP3A4 inhibitors. Concomitant use of ivabradine and diltiazem or verapamil is not recommended. Use with caution Other moderate CYP3A4 inhibitors (fluconazole and others). Treatment with ivabradine can be started with a dose of 2.5 mg 2 times a day. Heart rate monitoring is necessary. Drinking grapefruit juice is not recommended during treatment with ivabradine. Grapefruit juice can cause an increase in the concentration of ivabradine in the blood plasma and an increase in the effect relative to the decrease in heart rate. CYP3A4 stimulants such as 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 ivabradine and therefore there may be a need to adjust the dose of ivabradine. Other drugs Targeted drug interaction studies have demonstrated the absence of any clinically significant pharmacokinetic or pharmacodynamic interactions between ivabradine and the following drugs: HMG Co-A reductase inhibitors (simvastatin), proton pump inhibitors (omeprazole, lansoprazole), dihydropyridine calcium channel blockers (amlodipine). , lacidipine), digoxin and warfarin. Clinical studies have shown the possibility of using ivabradine with ACE inhibitors, angiotensin II antagonists, diuretics, short- and long-acting nitrates, fibrates, oral antidiabetic agents, acetylsalicylic acid and other antithrombotic drugs.