Description
Release form
Film-coated tablets.
Packing
56 pcs
Pharmacological action
ATX code: C01EV17.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamics
Ivabradine is a slowing heart rhythm drug whose mechanism of action is the selective and specific inhibition of If channels of the sinus node that 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 the impulses along the atrial, atrioventricular and intraventricular pathways, as well as the contractility of the myocardium and repolarization of the ventricles.
Ivabradine can also interact with Ih retinal channels, similar to If cardiac channels involved in the occurrence of a temporary change in the visual system due to a change in 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 light perception (photopsia). Photopsies are characterized by a transient change in brightness in a limited area of the visual field (see the section “Side effects”). The main pharmacological feature of ivabradine is the ability of a dose-dependent decrease in heart rate (HR). An analysis of the dependence of the rate of heart rate decrease on the dose of the drug was carried out with a gradual increase in the dose of ivabradine up to 20 mg twice a day and revealed a tendency to achieve the “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 40 bpm) (see the section “Side effects”).
When prescribing the drug in recommended doses, the degree of reduction in heart rate depends on its initial value and is approximately 10-15 beats / min at rest and during physical exertion. As a result, the work of the heart decreases and the need for myocardium in oxygen decreases.
Ivabradine does not affect intracardiac conduction, myocardial contractility (does not cause a negative inotropic effect), and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine did not affect the timing of the pulses along the atrioventricular or intraventricular pathways, as well as the adjusted QT intervals. In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%), it was shown that ivabradine does not affect myocardial contractility.
It was found that ivabradine in a dose of 5 mg 2 times a day improved the performance of exercise samples 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 with increasing doses from 5 to 7.5 mg 2 times a day was established in a comparative study with atenolol. The exercise time increased by about 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, a further increase in this indicator was noted for 25 seconds. The antianginal and anti-ischemic activity of ivabradine was also confirmed for 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 exercise samples (total duration of physical activity, time to the onset of a limiting angina attack, time to the onset of an angina attack and time to the development of ST segment depression on 1 mm), and was also accompanied by a decrease in the frequency of development of angina attacks by about 70%. The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours.
In patients taking ivabradine, additional efficacy of ivabradine was shown for all indicators of exercise samples when added to the maximum dose of atenolol (50 mg) in the decline in therapeutic activity (12 hours after ingestion).
The improvement in the effectiveness of ivabradine is not shown when adding to the maximum dose of amlodipine on the decline in therapeutic activity (12 hours after ingestion), while at the maximum activity (3 to 4 hours after ingestion) the additional effectiveness of ivabradine was proved.
In studies of the clinical efficacy of the drug, the effects of ivabradine were fully preserved throughout the 3 and 4 month treatment periods. During treatment, there were no signs of tolerance (decreased effectiveness), and after discontinuation of treatment, the “withdrawal” syndrome was not observed. The antianginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as with a significant decrease in the work product (heart rate Systolic blood pressure), and at rest, and during physical exertion. The effect on blood pressure (BP) and total peripheral vascular resistance (OPSS) was insignificant and clinically insignificant.
Sustained heart rate reduction has been 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.
There were no differences between the groups of patients taking ivabradine during standard therapy and in patients with stable angina pectoris and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers and placebo, according to the total mortality rate against cardiovascular disease, hospitalization for acute myocardial infarction, hospitalization for the occurrence of new cases of heart failure or increased symptoms of chronic heart failure (CHF) and in the subgroup of patients with heart rate of at least 70 beats / min. Against the background of the use of ivabradine in patients with heart rate of at least 70 beats / min. a 36% decrease in the hospitalization rate for fatal and non-fatal myocardial infarction and a 30% revascularization rate is shown.
Patients with angina pectoris while taking ivabradine showed a decrease in the relative risk of complications (the frequency of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of symptoms of heart failure) by 24% . The noted therapeutic advantage is achieved, first of all, by reducing the frequency of hospitalization for acute myocardial infarction by 42%.
The decrease in the frequency of hospitalization for fatal and non-fatal myocardial infarction in patients with a heart rate of more than 70 beats / min is even more significant and reaches 73%. In general, good tolerability and safety of the drug were noted.
With the use of ivabradine in patients with NYHA class II – IV functional class II CHF with LVEF, less than 35% showed a clinically and statistically significant decrease in the relative risk of complications (the frequency of deaths from cardiovascular diseases and a decrease in the hospitalization rate due to increased symptoms) CHF) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed after 3 months from the start of therapy.
A decrease in mortality from cardiovascular diseases and a decrease in the hospitalization rate due to an increase in symptoms of heart failure were observed regardless of age, gender, functional class of heart failure, use of beta-blockers, ischemic or non-ischemic etiology of heart failure, history of diabetes mellitus or arterial hypertension.
Patients with symptoms of heart failure with 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 inhibitors (ACE) and / or angiotensin II antagonist receptors (91%), diuretics (83%), and aldosterone antagonists (60%).
shown that the use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug. Against the background of the use of ivabradine, an improvement in the functional class of CHF according to NYHA classification is shown.
In patients with a heart rate of 80 bpm, a decrease in heart rate of 15 bpm was observed on average.
Pharmacokinetics
Ivabradine is an S-enantiomer with no bioconversion according to in vivo studies. The main active metabolite of the drug is the N-desmethylated derivative of ivabradine.
Absorption and bioavailability
Ivabradine is rapidly and almost completely absorbed in the gastrointestinal tract after oral administration. The maximum concentration (C max) in blood plasma is reached approximately 1 hour after ingestion on an empty stomach. Bioavailability is approximately 40%, which is due to the effect of the “first pass” through the liver.
Eating increases the absorption time by approximately 1 hour and increases the concentration in the blood plasma from 20% to 30%. To reduce the variability of the concentration, the drug is recommended to be taken simultaneously with food intake (see the section “Dosage and administration”).
Distribution of
Communication with plasma proteins is approximately 70%. The volume of distribution in equilibrium is about 100 liters. Cmax in blood plasma after prolonged use at a recommended dose of 5 mg 2 times a day is approximately 22 ng / ml (coefficient of variation = 29%). The average equilibrium plasma concentration is 10 ng / ml (coefficient of variation = 38%).
Metabolism Ivabradine is significantly metabolized in the liver and intestines by oxidation involving only cytochrome P450 3A4 (CYP3A4 isoenzyme). The main active metabolite is the N-desmethylated derivative (S 18982), the proportion of which is 40% of the dose of ivabradine concentration. The metabolism of the active metabolite of ivabradine also occurs in the presence of the CYP3A4 isoenzyme. Ivabradine has a low affinity for the CYP3A4 isoenzyme, does not induce or inhibit it. In this regard, ivabradine is unlikely to affect plasma metabolism or the concentration of substrates of the CYP3A4 isoenzyme. On the other hand, the simultaneous use of potent inhibitors or inducers of cytochrome P450 can significantly affect the concentration of ivabradine in blood plasma (see sections “Interaction with other medicinal products” and “Special instructions”).
Excretion
The elimination half-life (T1 / 2) of ivabradine is, on average, 2 hours (70-75% of the area under the concentration-time curve (AUC)), effective T1 / 2 is 11 hours. The total clearance is about 400 ml / min, renal – about 70 ml / min. Excretion of metabolites occurs at the same rate through the kidneys and intestines. About 4% of the dose taken is excreted by the kidneys unchanged.
Linearity and nonlinearity
The pharmacokinetics of ivabradine is linear in the dose range of 0.5 to 24 mg.
Indications
Stable angina pectoris
Therapy of stable angina pectoris in patients with normal sinus rhythm:
– in case of intolerance or contraindications to the use of beta-adrenergic blocking agents
in combination with beta-adrenergic blocking and non-stable adrenergic blockers Chronic heart failure
To reduce the incidence of cardiovascular complications (mortality from cardiovascular disease and hospitalization due to with increasing symptoms of heart failure) in patients with chronic heart failure, with sinus rhythm and heart rate of at least 70 beats / min.
Use during pregnancy and lactation
Coraxan is contraindicated for use during pregnancy. At the moment, there is insufficient data on the use of the drug during pregnancy. In preclinical studies of ivabradine revealed embryotoxic and teratogenic effects.
The use of Coraxan during breastfeeding is contraindicated. There is no evidence of the penetration of ivabradine into breast milk.
Composition
1 tablet of 5 mg contains: active substance: ivabradine hydrochloride 5.39 mg, which corresponds to 5.0 mg of base.
Excipients: lactose monohydrate 63.91 mg, magnesium stearate 0.5 mg, corn starch 20 mg, maltodextrin 10 mg, anhydrous colloidal silicon dioxide 0.20 mg.
Shell: glycerol 0.08740 mg, hypromellose 1.45276 mg, yellow iron oxide dye (E172) 0.01457 mg, red iron oxide dye (E172) 0.00485 mg, macrogol 6000 0.09276 mg, magnesium stearate 0.08740 mg, titanium dioxide (E171) 0.26026 mg.
Dosage and administration of
Coraxan should be taken orally 2 times a day, in the morning and in the evening during meals.
Stable angina pectoris. The recommended initial dose of the drug is 10 mg per day (1 tablet 5 mg 2 times a day).
Depending on the therapeutic effect, after 3-4 weeks of use, the daily dose of the drug can be increased to 15 mg (1 tablet 7.5 mg 2 times a day). If, during therapy with Coraxan®, heart rate at rest is reduced to values less than 50 beats / min, or the patient has symptoms associated with bradycardia (such as dizziness, increased fatigue, or a marked decrease in blood pressure), it is necessary to reduce the dose of Coraxan (for example, to 2 5 mg (1/2 tablet of 5 mg) 2 times a day). If, with a decrease in the dose of Coraxan, heart rate remains less than 50 beats / min, or symptoms of severe bradycardia persist, then the drug should be discontinued.
Chronic heart failure. The recommended initial dose of Coraxan is 10 mg per day (1 tablet 5 mg 2 times a day).
After two weeks of use, the daily dose of Coraxan can be increased to 15 mg (1 tablet 7.5 mg 2 times a day) if the heart rate at rest is stable for more than 60 beats / min. If the heart rate is stable no more than 50 beats / min or in case of symptoms of bradycardia, such as dizziness, increased fatigue or hypotension, the dose can be reduced to 2.5 mg (1/2 tablet 5 mg) 2 times a day .
If the heart rate is in the range from 50 to 60 beats / min, it is recommended to use the drug Coraxan in a dose of 5 mg 2 times a day.
If, during use of the drug, heart rate at rest is stably less than 50 beats / min or if the patient has symptoms of bradycardia, for patients receiving Coraxan in a dose of 5 mg 2 times a day or 7.5 mg 2 times a day, dose the drug should be reduced.
If patients receiving the drug Coraxan in a dose of 2.5 mg (1/2 tablet 5 mg) 2 times a day or 5 mg 2 times a day, heart rate at rest is stable over 60 beats / min, the dose of the drug may be increased.
If heart rate is not more than 50 beats / min or the patient has symptoms of bradycardia, the drug should be discontinued.
For patients 75 years of age and older, the recommended initial dose of Coraxan is 2.5 mg (1/2 tablet of 5 mg) 2 times a day. In the future, an increase in the dose of the drug is possible.
Impaired renal function. For patients with CC more than 15 ml / min, the recommended initial dose of Coraxan is 10 mg per day (1 tablet 5 mg 2 times a day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tablet 7.5 mg 2 times a day).
Due to a lack of clinical data on the use of Coraxan in patients with CC less than 15 ml / min, the drug should be used with caution.
Impaired liver function. For patients with a mild degree of liver failure (up to 7 points on the Child-Pugh scale), the usual dosage regimen is recommended. The recommended initial dose of Coraxan is 10 mg per day (1 tablet 5 mg 2 times a day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tablet 7.5 mg 2 times a day).
Side effects
On the part of the organ of vision:
Very often: changes in light perception (photopsy): was observed in 14.5% of patients and was described as a transient change in brightness in a limited area of the visual field. As a rule, such phenomena were provoked by a sharp change in the intensity of illumination in the area of the visual field. Basically, photopsia appeared in the first two months of treatment, followed by a repeat. The severity of photopsia was usually mild or moderate. The appearance of photopsy ceased on the background of continued therapy (in 77.5% of cases) or after its completion. In less than 1% of patients, the appearance of photopsy was the reason for refusing treatment.
Often: blurred vision.
From the cardiovascular system: Often: bradycardia: in 3.3% of patients, especially in the first 2-3 months of therapy, in 0.5% of patients developed severe bradycardia with a heart rate of not more than 40 beats / min AV block of the first degree ventricular extrasystole.
Infrequently: palpitations, supraventricular extrasystole.
Unspecified frequency: arterial hypotension, possibly associated with bradycardia
The following adverse events identified in clinical trials occurred with the same frequency both in the group of patients treated with ivabradine and in the comparison group, which suggests their association with the disease as such, and not with ivabradine: sinus arrhythmia, angina pectoris, including unstable atrial fibrillation, myocardial ischemia, myocardial infarction and ventricular tachycardia.
From the digestive system: infrequently: nausea, constipation, diarrhea.
From the central nervous system:
Often: headache, especially in the first month of therapy, dizziness, possibly associated with bradycardia.
Infrequently: shortness of breath, vertigo, muscle spasms.
Unspecified frequency: fainting, possibly associated with bradycardia.
Laboratory indicators: infrequently: hyperuricemia, eosinophilia, increased plasma creatinine concentration.
From the skin and subcutaneous fat: skin rash, itching, erythema, angioedema, urticaria.
General disorders and symptoms: asthenia, fatigue, malaise, possibly related to bradycardia.
Drug Interaction
Pharmacodynamic Interaction
Not recommended combinations of
drugs that prolong the QT interval (eg quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).
drugs that prolong the QT interval, not related to cardiovascular agents (eg pimozide, ziprasidone, sertindol, mefloquine, halofantrine, pentamidine, cisapride, erythromycin IV).
Co-administration with drugs that prolong the QT interval may increase the rate of heart rate, so careful cardiac monitoring should be performed when required jointly.
Pharmacokinetic interaction of
Cytochrome P4503A4 (CYP3A4). Ivabradine is metabolized in the liver by enzymes of the cytochrome P450 (CYP3A4) system and is a very weak inhibitor of this cytochrome. Ivabradine has no significant effect on the metabolism and plasma concentration of other cytochrome CYP3A4 substrates. At the same time, CYP3A4 inhibitors and inducers interact with ivabradine and affect its metabolism and pharmacokinetic properties. Cytochrome CYP3A4 inhibitors have been found to increase and cytochrome CYP3A4 inducers decrease ivabradine plasma concentrations. Increasing the concentration of ivabradine in blood plasma increases the risk of developing pronounced bradycardia. srdlcp
contraindications Use with strong cytochrome P450 inhibitors such as antifungal, azetone (ketoconazole, itraconazole), macrolide, clarithromycin, erythromycin , ketoconazole (at a dose of 200 mg 1 time a day) or mozamycin (at a dose of 1 g 2 times a day) increase the average plasma concentrations of ivabradine 7-8 times.
Not recommended combinations
Moderate CYP3A4 inhibitors. The combined use of ivabradine and heart rate-reducing agents – diltiazem or verapamil, was well tolerated by patients and was accompanied by an increase in ivabradine concentration of 2-3 times, with an additional reduction of heart rate of approximately 5 beats / min.
This combination is not recommended.
Cautions when using
Moderate-acting CYP3A4 inhibitors. Concomitant administration of ivabradine with other CYP3A4 inhibitors (eg fluconazole) should be initiated with an initial dose of 2.5 mg twice daily. At a heart rate of at least 60 beats / min, careful monitoring of the heart rate is required.
Grapefruit juice. Against the background of grapefruit juice, there was a 2-fold increase in the concentration of ivabradine in the blood. Grapefruit juice should be kept to a minimum during ivabradine therapy.
CYP3A4 inducers, such as rifampicin, barbiturates, phenytoin, and herbal preparations containing Hypericum perforatum, combined with Hypericum perforatum, may result in decreased blood concentrations and ivabradine activity and may require a higher dose selection. During the period of ivabradine therapy, the use of drugs and products containing perforated St. John’s wort should be minimized.
Combined use with other medicines
The lack of a clinically pronounced effect on the pharmacodynamics and pharmacokinetics of ivabradine of the following drugs has been demonstrated: proton pump inhibitors (omeprazole, lansoprazole), phosphodiesterase-5 inhibitors (sildenafil), HMG-CoA reductase inhibitors (simvastatin), BKK-derivatives of the dihydropyridine series (amlodipine, lacidipine), dicidipine
It has been shown that ivabradine has no clinically pronounced effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin, and the pharmacodynamics of acetylsalicylic acid.
In the Phase III pilot study, the use of the following medicines did not have any specific limitations, so they can be given in combination with ivabradine without special precautions: ACE inhibitors, angiotensin II receptor antagonists, diuretics, short acting G and nitongi -CoA reductase, fibrates, proton pump inhibitors, oral hypoglycemic agents, acetylsalicylic acid and other antithrombotic agents.
Overdose
Symptoms: severe and prolonged bradycardia.
Treatment of marked bradycardia should be symptomatic and carried out in specialized wards. In the case of bradycardia, in combination with disorders of hemodynamics, symptomatic treatment with intravenous administration of beta-adrenomimetics such as isoprenaline has been shown.
If necessary, it is possible to set an artificial rhythm driver.
Storage conditions
No special storage conditions are required. Out of the reach of children.
The Expiration of
is 3 years.
Deystvuyuschee substances
Yvabradyn
dosage form
dosage form
tablets
Servye, France
