Description of the drug IVABRADIN-LF
When used together with ivabradine drugs that increase the QT interval (quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin IV), an increase in heart rate reduction and additional prolongation of the QT interval. If simultaneous therapy is necessary, ECG readings should be carefully monitored (such combinations are not recommended).
Ivabradine is metabolized in the liver with the participation of the CYP3A4 isoenzyme and is a very weak inhibitor of this isoenzyme. Ivabradine does not have a significant effect on the metabolism and plasma concentrations of other substrates (strong, moderate and weak inhibitors) of cytochrome CYP3A4. At the same time, inhibitors and inducers of the CYP3A4 isoenzyme can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It has been found that inhibitors of the CYP3A4 isoenzyme increase, and inducers of the CYP3A4 isoenzyme reduce, plasma concentrations of ivabradine. Increasing the concentration of ivabradine in blood plasma may increase the risk of developing severe bradycardia.
Concomitant use with strong inhibitors of the CYP3A4 isoenzyme, such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir, nefazodone) is contraindicated due to increased concentrations ivabradine in blood plasma and the risk of developing excessive bradycardia.
The simultaneous use of ivabradine and moderate inhibitors of the CYP3A4 isoenzyme diltiazem or verapamil (drugs that slow heart rate) in healthy volunteers and patients was accompanied by an increase in the AUC of ivabradine by 2-3 times and an additional decrease in heart rate by 5 beats/min. These combinations are not recommended.
Inducers of the CYP3A4 isoenzyme, such as rifampicin, barbiturates, phenytoin and herbal preparations containing St. John's wort (Hypericum perforatum), when used together with ivabradine, may lead to a decrease in the blood concentration and activity of ivabradine (a higher dose of the drug may be required). With the combined use of ivabradine and preparations containing St. John's wort, a twofold decrease in the AUC of ivabradine was noted. During the period of use of ivabradine, the intake of herbal preparations containing St. John's wort should be reduced.
The use of ivabradine in combination with other moderate inhibitors of the CYP3A4 isoenzyme (for example, fluconazole) is possible provided that the resting heart rate is more than 60 beats/min. The recommended starting dose of ivabradine is 2.5 mg 2 times a day. Heart rate control is required.
Ivabradine should be used with caution with non-potassium-sparing diuretics (thiazide and loop diuretics), because Hypokalemia may increase the risk of developing arrhythmia. Because ivabradine can cause bradycardia, the combination of hypokalemia and bradycardia is a predisposing factor for the development of severe arrhythmia, especially in patients with long QT syndrome, either congenital or caused by exposure to any substances.
When drinking grapefruit juice while taking ivabradine, there was a 2-fold increase in the concentration of ivabradine in the blood. During ivabradine therapy, grapefruit juice intake should be reduced.
Ivabradine, 5 mg, film-coated tablets, 56 pcs.
Ivabradine is a drug that slows the heart rate, the mechanism of action of which is to selectively and specifically suppress the If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate (HR).
The action is specific to the sinus node and does not affect the timing of impulses along the intraatrial, atrioventricular and intraventricular pathways, as well as myocardial contractility. The processes of ventricular repolarization remain unchanged.
Ivabradine can also interact with the cardiac If channels, Ih channels of the retina, which are involved in the occurrence of 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), partial inhibition of Ih channels by ivabradine causes the so-called phenomenon of changes in light perception (photopsia). Photopsia is characterized by a transient change in brightness in a limited area of the visual field.
The main pharmacological feature of ivabradine is its ability to dose-dependently reduce heart rate. 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), which reduces the risk of developing severe, poorly tolerated bradycardia (heart rate less than 40 beats/min).
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) or the processes of repolarization of the ventricles of the heart. In clinical electrophysiological studies, ivabradine had no effect on the conduction time of impulses along the atrioventricular or intraventricular pathways, nor on the corrected QT interval.
In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%), it was shown that ivabradine does not affect myocardial contractile function.
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.
The time for performing physical activity increases by approximately 1 minute after just 1 month of using ivabradine 5 mg 2 times a day, while after an additional 3 months of taking ivabradine at a dose of 7.5 mg 2 times a day, a further increase of this indicator by 25 seconds was noted.
The antianginal and anti-ischemic efficacy of ivabradine was also confirmed in patients aged 65 years and older.
The effectiveness of ivabradine 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 development of the ST segment by 1 mm), and was also accompanied by a decrease in the incidence of angina attacks by 70%.
The use of ivabradine 2 times a day provided constant therapeutic efficacy over 24 hours.
In patients taking ivabradine, additional effectiveness 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 a clinical efficacy study, 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 work product (heart rate * systolic blood pressure), both at rest and during physical activity. 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 (CAD) without clinical manifestations of heart failure (LVEF greater than 40%) during maintenance therapy, treatment with ivabradine at doses higher than recommended (initial dose 7.5 mg twice daily (5 mg twice daily) day over age 75 years), which was then titrated to 10 mg twice daily) had no significant effect on the primary composite endpoint of cardiovascular death or nonfatal myocardial infarction. The incidence of bradycardia in the group of patients receiving ivabradine was 17.9%.
In patients with Canadian Cardiological Society functional class II or higher angina, there was an increase in the incidence of the primary composite endpoint with ivabradine, which was not observed in the subgroup of all patients with angina (functional class I or higher).
In a study involving 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: patients taking ivabradine against the background of standard therapy and placebo, in terms of the total incidence deaths from cardiovascular diseases, hospitalizations for acute myocardial infarction, hospitalizations for new cases of heart failure or worsening symptoms of chronic heart failure (CHF).
Among patients with angina, there were no significant differences in the incidence of death due to a cardiovascular cause or hospitalization due to nonfatal myocardial infarction or heart failure.
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 exertional angina pectoris while taking ivabradine, there was a reduction in the relative risk of complications (the incidence of deaths from cardiovascular diseases, hospitalizations for acute myocardial infarction, hospitalizations 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 hospitalizations for acute myocardial infarction by 42%. The reduction in the frequency of hospitalizations 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, ivabradine 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 decrease in the relative risk of complications (the incidence of deaths from cardiovascular diseases and a decrease in the number of hospitalizations due to increased symptoms of 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.
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.
Ivabradine canon TB p/o captivity 5mg N 56
Active substance
Ivabradin
pharmachologic effect
Antianginal agent. The mechanism of action is the selective and specific inhibition of If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate.
Ivabradine has a selective effect on the sinus node, without affecting the timing of impulses along the intraatrial, atrioventricular and intraventricular pathways, as well as myocardial contractility and ventricular repolarization.
The main pharmacodynamic property of ivabradine is a specific, dose-dependent decrease in heart rate. Analysis of the dependence of the magnitude of the decrease in heart rate at a dose of more than 20 mg 2 times / day revealed a tendency to achieve a plateau effect, which reduces the risk of developing severe, poorly tolerated bradycardia (heart rate less than 40 beats / min).
When used in recommended doses, the decrease in heart rate 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 is also able to interact with the Ih channels of the retina, similar to the If channels of the heart. The Ih channel is involved in the occurrence of temporary changes in the resolution of the visual system, because reduces the retinal response to bright light stimuli. Under provoking circumstances (eg, rapid changes in brightness), ivabradine partially inhibits the electrical impulse Ih, which sometimes leads to the appearance of light sensations (phosphenes) in some patients, which are described as a short-term sensation of increased brightness in a limited part of the visual field.
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 incidence of deaths from cardiovascular diseases and a reduction in the frequency of hospitalizations due to increased symptoms CHF) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months after the start of therapy.
Indications of the active substances of the drug Ivabradine Canon
Treatment of stable angina in patients with normal sinus rhythm: with intolerance or contraindications to the use of beta-blockers; in combination with beta-blockers with inadequate control of stable angina pectoris against the background of the optimal dose of beta-blocker.
Chronic heart failure: to reduce the incidence of cardiovascular complications in patients with chronic heart failure, with sinus rhythm and heart rate of at least 70 beats/min.
Dosage regimen
The average recommended starting dose of ivabradine is 5 mg 2 times / day (10 mg / day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose can be increased to 7.5 mg 2 times / day (15 mg / day).
If during therapy the heart rate decreases to values less than 50 beats/min or symptoms associated with bradycardia occur (such as dizziness, fatigue or hypotension), a lower dose should be selected; if necessary, the dose can be reduced to 2.5 mg 2 times / day. If the heart rate remains less than 50 beats/min and the symptoms of bradycardia do not go away, then treatment is stopped.
In elderly patients, it is recommended to start treatment with an initial dose of 2.5 mg 2 times a day. In the future, it is possible to increase the daily dose depending on the patient’s condition.
Before use, consultation with a specialist is required.
The method of administration and dosage regimen of a particular drug depend on its release form and other factors. The optimal dosage regimen is determined by the doctor.
Storage mode, interactions and side effects are indicated in the instructions.
Contraindications for use
Bradycardia (heart rate at rest below 60 beats/min before treatment); cardiogenic shock; acute myocardial infarction; severe arterial hypotension (systolic blood pressure below 90 mmHg and diastolic blood pressure below 50 mmHg); severe liver failure (more than 9 points on the Child-Pugh scale); SSSU; sinoatrial block; chronic heart failure of functional class III and IV according to the NYHA classification; the presence of an artificial pacemaker operating in constant stimulation mode; unstable angina; AV block of the third degree; pregnancy; lactation period (breastfeeding); children and adolescents up to 18 years of age; simultaneous use with strong inhibitors of the CYP3A4 isoenzyme, such as antifungals of the azole group (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin for oral administration, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone; hypersensitivity to ivabradine.
Contraindications
The medicine has certain restrictions on its use.
It cannot be used:
- for myocardial infarction ;
- persons suffering from 3rd degree AV block
- patients with severely low blood pressure ;
- with bradycardia ;
- patients with cardiogenic shock ;
- with serious disorders of the liver;
- persons with sick sinus syndrome ;
- with sinoatrial block ;
- patients with chronic heart failure classes 3 and 4 ( NYHA );
- during breastfeeding;
- patients with an artificial pacemaker who is in constant stimulation mode;
- for unstable angina ;
- pregnant women;
- if you are allergic to Ivabradine;
- children and adolescents under 18 years of age.
Chemical properties
Ivabradine is the first substance - an inhibitor of if-channels , which has a specific and selective effect. Its development became possible after the discovery in 1980 of ionic if channels , which are responsible for heart rate. By 2005, the substance was approved for use in the treatment of stable angina in normal sinus rhythm , in patients intolerant to other drugs. Next, it was decided to use the compound in combination with beta-blockers .
In medications, this component is usually present in the form of ivabradine hydrochloride .
special instructions
It is best to prescribe the drug if the course of heart failure is stable. Caution must be observed in case of intraventricular conduction or ventricular dyssynchrony .
The drug is not prescribed for the treatment of arrhythmias ; it is insufficiently effective.
During treatment with this substance, it is recommended to periodically do an ECG in order to promptly detect atrial fibrillation . If the course of angina pectoris , a feeling of palpitations, or a shift in heart rhythm, it is recommended to stop taking the medication and prescribe adequate therapy.
Ivabradine should be stopped the day before electrical cardioinversion .
During treatment, it is not recommended to drive a car; it should be remembered that the drug distorts the eye’s perception of light, especially at night.
Indications for use
Ivabradine is prescribed:
- for the treatment of stable angina in patients with normal sinus rhythm , if there is an allergy to beta-blockers or contraindications to their use;
- in combination with beta blockers to control stable angina ;
- for chronic heart failure , to reduce the incidence of complications if the heart rate is less than 70 beats per minute.
Side effects
During therapy, depending on the frequency of occurrence, the following may be observed:
- photopsia (impaired perception of the degree of illumination);
- bradycardia , decreased visual acuity, vertigo , AV block ;
- extrasystoles , headaches, dizziness;
- sometimes - nausea, palpitations, diarrhea , constipation , shortness of breath ;
- diplopia , atrial fibrillation , syncope;
- muscle cramps eosinophilia , hyperuricemia , hypercreatininemia .
Also, no connection has been established between the occurrence of the following adverse reactions and taking Ivabradine: unstable angina , atrial fibrillation , myocardial infarction , ventricular tachycardia , sinus arrhythmia , exacerbation of angina , myocardial ischemia .
Pharmacodynamics and pharmacokinetics
The substance has the ability to specifically and selectively block the work of if-channels in the sinus node, which are responsible for controlling diastolic depolarization and regulating heart rate . The drug does not affect the atrioventricular, intraatrial and intraventricular pathways, does not change the contractility of the heart muscle, and does not alter the process of repolarization .
The effect of the drug is dose-dependent, the likelihood of developing bradycardia is significantly reduced. The medicine reduces heart rate at rest by about 10 beats per minute, heart work becomes less intense, and the amount of oxygen consumed by the heart muscle decreases.
The substance interacts with ih channels in the retina, which are similar in structure to if channels in the heart, as a result of which the sensitivity of the retina to bright light pulses changes. Photopsia occurs .
During treatment with the drug, tolerance or withdrawal syndrome to this substance does not develop. The drug does not affect blood pressure and total peripheral vascular resistance, lipid and carbohydrate metabolism does not change.
After oral administration, the active substance is quickly and completely absorbed. Its bioavailability reaches 40%, this is due to the “first pass” effect through the liver. With a parallel meal, an increase in systemic absorption time by 60 minutes is observed. The maximum concentration is observed within 1.5 hours after taking the medicine. About 70% of the substance binds to plasma proteins.
The drug undergoes metabolic reactions in the intestines and liver due to oxidation under the influence of the CYP3A4 isoenzyme. The main active metabolite of the compound is formed due to N-desmethylation .
The half-life of the drug is about 2 hours, the effective half-life is 11. The elimination of the unchanged substance, its inactive and active metabolites occurs through the kidneys and intestines.
In kidney diseases, pharmacokinetic parameters change slightly. The AUC of Ivabradine and its metabolite increases by 20%.
Ivabradine, instructions for use (Method and dosage)
Ivabradine tablets are prescribed to be taken 2 times a day, in the morning and before bedtime, preferably during meals.
It is recommended to start with a dosage of 10 mg per day, divided into 2 doses of 5 mg. If necessary and depending on the effectiveness of therapy, after 3-4 weeks you can increase the dosage to 15 mg per day.
If during treatment there is the development of undesirable side reactions, fatigue, bradycardia , decreased blood pressure , dizziness, then the daily dosage is recommended to be reduced to 5 mg per day, the frequency of administration is the same.
If the heart rate becomes less than 50 beats per minute, treatment should be stopped.
For elderly patients, dosage adjustment is recommended. It is recommended to take 2.5 mg of the drug, 2 times a day. If the substance has a beneficial effect on the body, the daily dosage can be increased after a month.
