Raenom - instructions for use, doses, side effects, contraindications, price, where to buy

Raenom®

Ivabradine is a medicine that slows the heart rate.

The mechanism of action of ivabradine is the selective and specific inhibition of I

ƒ 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 conduction time of impulses along the intraatrial, atrioventricular and intraventricular pathways, as well as on myocardial contractility and ventricular repolarization.

Ivabradine may also interact with Ih

channels of the retina, similar in structure to
the If
channels of the heart. They are involved in the mechanisms of temporary adaptation of the visual perception system by changing the retinal response to bright light stimuli.

Under provoking circumstances (for example, a sharp change in illumination intensity in the visual field), partial inhibition of Ih

channels with ivabradine leads to
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 effect of ivabradine is a dose-dependent decrease in 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 2 times a day and revealed a tendency to achieve a “plateau” effect (no increase in the therapeutic effect with a further increase in the dose of the drug), which reduces the risk of developing severe bradycardia (HR less than 40 beats/min) (see section “Side effects”).

When using the drug in recommended doses, the degree of decrease in heart rate depends on its initial value and is approximately 10-15 beats/min both at rest and during physical activity, as a result of which the work of the heart and the myocardial oxygen demand decreases.

Ivabradine does not affect intracardiac conduction, myocardial contractility (does not have a negative inotropic effect) and the process of ventricular repolarization. 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 in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%) it was shown that ivabradine does not affect myocardial contractility.

The antianginal and anti-ischemic activity of ivabradine has also been 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 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 was shown in relation to all indicators of stress tests when added to the maximum dose of atenolol (50 mg) at the decline of its therapeutic activity (12 hours after oral administration).

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

In studies of the clinical effectiveness of ivabradine, its therapeutic effect was fully maintained over 3-4 months of therapy. During treatment, there were no signs of decreased effectiveness, and after cessation of treatment, no withdrawal syndrome was observed.

The antianginal and anti-ischemic effects of ivabradine were associated with both a dose-dependent decrease in heart rate and 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 who took 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 population. There were no differences between the groups of patients taking ivabradine against the background of standard therapy, and in patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers and placebo, in the total incidence of cardiac deaths -vascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of chronic heart failure (CHF) and in the subgroup of patients with a heart rate of at least 70 beats/min.

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%.

The noted therapeutic benefit is achieved primarily by reducing the frequency of hospitalizations for acute myocardial infarction by 42%. The reduction in the rate 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 incidence of deaths from cardiovascular diseases and a reduction in the frequency of hospitalizations due to worsening CHF ) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months after the start of ivabradine therapy.

A decrease in mortality from cardiovascular diseases and the frequency of hospitalizations due to worsening 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, which included 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 NYH A 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.

Instructions for use of RAENOM®

No effect on clinical outcomes in patients with symptomatic chronic stable angina

Raenom® is indicated only for the symptomatic treatment of chronic stable angina, as it does not have a beneficial effect on cardiovascular outcomes (eg, myocardial infarction or cardiovascular mortality).

Heart rate control

Taking into account the variability of heart rate throughout the day, periodic heart rate measurements, ECG or 24-hour monitoring should be considered to determine resting heart rate before starting treatment with Raen®, as well as in patients receiving treatment with ivabradine when dose titration is necessary . This also applies to patients with low heart rate, in particular when heart rate is less than 50 beats/min, or when the dose is reduced (see Dosage Regimen).

Heart rhythm disturbances

Raenom® is not effective for the treatment or prevention of arrhythmias. There is a high probability of a decrease in its effectiveness due to the development of tachyarrhythmia (for example, ventricular or supraventricular tachycardia). Therefore, Raenom® is not recommended for patients with atrial fibrillation or other types of cardiac arrhythmias associated with sinus node function.

Patients receiving treatment with Raen® have an increased risk of developing atrial fibrillation. Atrial fibrillation was more common among patients who were taking amiodarone or class I antiarrhythmic drugs concomitantly with ivabradine. It is recommended to conduct regular clinical monitoring of patients receiving treatment with Raen® for the detection of atrial fibrillation (persistent or paroxysmal), which, if clinically indicated, should also include ECG monitoring (for example, in the case of worsening angina, palpitations, irregular pulse).

Patients should be informed about the signs and symptoms of atrial fibrillation and should be advised to seek medical attention if such symptoms occur.

If atrial fibrillation occurs during therapy, it is necessary to assess the benefit-risk ratio of further treatment with Raen®.

Patients with CHF and intraventricular conduction disorders (left bundle branch block, right bundle branch block) and ventricular dyssynchrony should be closely monitored.

2nd degree AV block

Prescribing Raenom® to patients with second degree AV block is not recommended.

Use in patients with bradycardia

Raenom® should not be prescribed to patients if, before starting therapy, the resting heart rate is less than 70 beats/min.

If during therapy the resting heart rate decreases to values less than 50 beats/min or the patient experiences symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), the dose of the drug must be reduced. If, when the dose of the drug is reduced, the heart rate remains less than 50 beats/min or symptoms of bradycardia persist, the drug should be discontinued.

Combination therapy with calcium channel blockers

The use of Raenom® in combination with calcium channel blockers (CCBs) that reduce heart rate, such as verapamil or diltiazem, is contraindicated. When using the drug Raenom® in combination with nitrates and dihydropyridine CCBs, such as amlodipine, no changes in the safety profile were noted. It has not been established that simultaneous use with CCBs increases the effectiveness of ivabradine.

Chronic heart failure

The use of Raenom® should be considered only in cases of stable CHF. Caution should be exercised when using the drug Raenom® in patients with NYHA functional class IV CHF due to limited data on the use of the drug in this group of patients.

Stroke

It is not recommended to use the drug Raenom® immediately after a stroke, because There are no data on the use of the drug in such situations.

Functions of visual perception

Ivabradine affects the function of the retina. There is no evidence that ivabradine treatment causes long-term retinal toxicity. If visual impairments not described in these instructions occur, you should consider stopping the drug. Caution should be exercised when prescribing Raenom® to patients with retinal pigmentary degeneration.

Arterial hypotension

There is insufficient data on use in patients with mild or moderate arterial hypotension, so caution should be exercised when prescribing Raenom® to such patients. Raenom® is contraindicated in patients with severe arterial hypotension (BP < 90/50 mm Hg).

Atrial fibrillation

–
cardiac arrhythmias
There was no risk of developing severe bradycardia while taking ivabradine when restoring sinus rhythm through pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to delay elective electrical cardioversion, Raenom should be discontinued 24 hours before it is performed.

Congenital long QT syndrome or treatment with drugs that prolong the QT interval

Avoid prescribing Raenom® to patients with congenital long QT syndrome or patients taking drugs that prolong the QT interval. If it is necessary to use such a combination, careful monitoring of cardiac function should be performed.

The reduction in heart rate caused by ivabradine may exacerbate the prolongation of the QT interval, which can cause the development of severe arrhythmias, in particular, torsades de pointes (TdP).

Patients with arterial hypertension requiring adjustment of antihypertensive therapy

In the SHIFT study, increased blood pressure was more common in the ivabradine group (7.1%) compared with placebo (6.1%). Most often, these cases were observed immediately after changing antihypertensive therapy; they were temporary and did not affect the effectiveness of ivabradine. When changing antihypertensive therapy in patients with CHF taking ivabradine, blood pressure monitoring is necessary at appropriate time intervals.

Excipients

Raenom® film-coated tablets,

contain lactose.

The drug is not recommended for patients with lactase deficiency, lactose intolerance, or glucose-galactose malabsorption syndrome.

Impact on the ability to drive vehicles and machinery

A special study to evaluate the effect of ivabradine on the ability to drive a car was conducted with the participation of healthy volunteers. According to its results, the ability to drive a car did not change. However, in the post-registration period, there were cases of deterioration in the ability to drive vehicles due to symptoms associated with visual impairment. Ivabradine may cause a temporary change in light perception, predominantly in the form of phosphenes. The possible occurrence of such a change in light perception should be taken into account when driving vehicles or other mechanisms when there is a sharp change in light intensity, especially at night.

Ivabradine does not affect the ability to operate machinery.

Raenom tablets po 5 mg No. 14x4

Name

Raenom tab p/capt. about. 5 mg per bl. in pack No. 14x4

Main active ingredient

Ivabradin

Release form

Pills

Compound

Each film-coated tablet contains: Dosage 5 mg Active ingredient: ivabradine? 5 mg (as ivabradine hydrobromide 5.863 mg); Excipients: lactose, mannitol (E421), maltodextrin, croscarmellose sodium, colloidal anhydrous silicon dioxide (E551), magnesium stearate. Tablet shell: Opadry 200F240001 pink: polyvinyl alcohol (E1203), talc (E553b), titanium dioxide (E171), macrogol / PEG 3350 (E1521), methacrylic acid? ethyl acrylate copolymer (1:1), iron oxide yellow (E172), iron oxide red (E172), sodium bicarbonate (E500). Dosage 7.5 mg Active ingredient: ivabradine? 7.5 mg (as ivabradine hydrobromide 8.795 mg); Excipients: lactose, mannitol (E421), maltodextrin, croscarmellose sodium, colloidal anhydrous silicon dioxide (E551), magnesium stearate. Tablet shell: Opadry 200F240001 pink: polyvinyl alcohol (E1203), talc (E553b), titanium dioxide (E171), macrogol / PEG 3350 (E1521), methacrylic acid? ethyl acrylate copolymer (1:1), iron oxide yellow (E172), iron oxide red (E172), sodium bicarbonate (E500).

Description

Dosage 5 mg Light orange, oval, biconvex film-coated tablets, with two V-shaped scoring lines on the sides, engraved “SKZ” on one side, the other side without engraving. Dimensions: ~8.6mm x 4.5mm. The tablet can be divided into two equal doses. Dosage 7.5 mg Light orange, round, biconvex film-coated tablets, engraved “CK4” on one side, unengraved on the other side. Diameter: ~6 mm.

Dosage

5 mg and 7.5 mg

Pharmacological properties

Pharmacodynamics

Mechanism of action of Ivabradine? 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 the heart rate (HR). The drug 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 can also interact with the Ih channels of the retina, which are similar in structure to the If channels of the heart. They are involved in the mechanisms of temporary adaptation of the visual perception system by changing the retinal response to bright light stimuli. Under certain circumstances (for example, sudden changes in light intensity), ivabradine partially inhibits Ih, which sometimes leads to the phenomenon of altered light perception in some patients. Such phenomena of changes in light perception (phosphenes) are characterized by a short-term sensation of increased brightness in a limited area of the visual field (see section “Side effects”). 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 up to 20 mg twice a day revealed a tendency to achieve a “plateau” effect, which reduces the risk of developing severe bradycardia (less than 40 beats/min). When using ivabradine in recommended doses, the degree of decrease in heart rate both at rest and during physical activity is approximately 10 beats/min. This leads to a decrease in the load on the heart and a decrease in the myocardial oxygen demand. Ivabradine does not affect intracardiac conduction, contractility (does not have a negative inotropic effect) and the process of ventricular repolarization: ? clinical electrophysiological studies have shown that ivabradine does not affect the timing of impulses along the atrioventricular or intraventricular pathways, as well as the corrected QT intervals; ? in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30 to 45%), ivabradine did not have a negative effect on LVEF. Clinical efficacy and safety The antianginal and anti-ischemic effects of ivabradine were studied in five double-blind randomized studies (three compared with placebo and one each compared with atenolol and amlodipine). A total of 4,111 patients with stable angina participated in these studies; 2,617 of them received ivabradine. It was found that ivabradine at a dose of 5 mg twice a day improved the performance of stress tests by 3? 4 weeks of treatment. The effectiveness of a dosage of 7.5 mg twice daily was also confirmed. In particular, in a comparative study using atenolol, an additional effect was found when increasing the dose from 5 mg to 7.5 mg twice daily: exercise time increased by approximately 1 minute after 1 month of use of ivabradine at a dose of 5 mg twice daily 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 by 25 seconds was noted. The antianginal and anti-ischemic efficacy of ivabradine has also been confirmed in patients aged 65 years and older. The effectiveness of dosages of 5 and 7.5 mg twice daily was observed throughout all studies in relation to all indicators of stress tests (total duration of physical activity, time to limiting angina attack, time to onset of angina attack and time to development of ST segment depression at 1 mm) and was accompanied by a decrease in the incidence of angina attacks by approximately 70%. Twice-daily administration of ivabradine provided consistent therapeutic efficacy over 24 hours. In studies of the clinical effectiveness of ivabradine, its therapeutic effect was fully maintained for 3? 4 months of therapy. There were no signs of the development of pharmacological tolerance (loss of effectiveness) during treatment or withdrawal syndrome upon sudden cessation of treatment. The antianginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate and a significant decrease in the double product (heart rate x systolic blood pressure) both at rest and during exercise. The effect on blood pressure and peripheral vascular resistance was minor and not clinically significant. A consistent reduction in heart rate was demonstrated in patients who received ivabradine for at least one year. No effect on carbohydrate metabolism and lipid profile was observed. The antianginal and anti-ischemic effects of ivabradine were maintained in patients with diabetes mellitus, and the safety profile was similar to that in the general population.

Pharmacokinetics

Under physiological conditions, ivabradine is rapidly released from the tablet and is highly soluble in water (> 10 mg/ml). Ivabradine is an S-enantiomer with no signs of bioconversion (according to in vivo studies). It was found that the main active metabolite is the N-desmethylated derivative of ivabradine. Absorption and bioavailability Ivabradine is rapidly and almost completely absorbed after oral administration, with maximum plasma concentrations achieved after approximately 1 hour when taken on an empty stomach. The absolute bioavailability of film-coated tablets is about 40% due to “first pass” through the intestines and liver. Eating slows down absorption by approximately 1 hour and increases plasma concentrations by 20–30%. It is recommended to take the tablet with food to reduce intra-individual variability in concentration (see section "Dosage and Administration"). Distribution Ivabradine is approximately 70% bound to plasma proteins, and the volume of distribution in patients at steady state is close to 100 liters. The maximum concentration (Cmax) in blood plasma with continuous use at the recommended dose of 5 mg twice a day is 22 ng/ml (coefficient of variation (CV) = 29%). The average plasma concentration is 10 ng/ml (CV = 38%). Biotransformation Ivabradine is predominantly metabolized in the liver and intestines by oxidation with the participation of cytochrome P450 3A4 (CYP3A4). The main active metabolite is the N-desmethylated derivative (S 18982), the concentration of which is approximately 40% of the ivabradine dose. The CYP3A4 isoenzyme is also involved in the metabolism of this active metabolite. Ivabradine has low affinity for CYP3A4 and is not clinically significant and does not induce or inhibit CYP3A4 and is therefore unlikely to alter the metabolism or plasma concentrations of CYP3A4 substrates. Conversely, potent inhibitors and inducers of the isoenzyme can significantly affect the concentration of ivabradine in the blood plasma (see section “Interaction with other drugs”). Elimination The main half-life of ivabradine from blood plasma is 2 hours (70-75% AUC), and the effective half-life is ? 11 o'clock. The total clearance is approximately 400 ml/min, renal clearance is ? about 70 ml/min. Excretion of metabolites occurs to the same extent in urine and feces. About 4% of the oral dose is excreted unchanged in the urine. Linearity/nonlinearity The kinetics of ivabradine are linear over the oral dose range from 0.5 to 24 mg. Pharmacokinetics in certain groups of patients Elderly patients Pharmacokinetic parameters (AUC and Cmax) do not differ in groups of elderly patients? 65 years) or very elderly (? 75 years) and the general patient population (see section "Dosage and Administration"). Impaired renal function The effect of renal failure (creatinine clearance from 15 to 60 ml/min) on the pharmacokinetics of ivabradine is very limited, this is due to the low participation of renal clearance (about 20%) in the total elimination of ivabradine and its main metabolite S 18982 (see section " Method of administration and dosage"). Impaired liver function In patients with mild hepatic impairment (up to Child-Pugh score 7), the AUC of free ivabradine and the main active metabolite was approximately 20% higher than in patients with normal liver function. Data on the use of the drug in patients with moderate hepatic impairment are limited. There are no data on the use of the drug in patients with severe liver failure (see sections “Dosage and Administration” and “Contraindications”). Pediatric Population The pharmacokinetic profile of ivabradine in children with chronic heart failure aged 6 months to 18 years is similar to the pharmacokinetics described in adults when the titration schedule is based on age and weight. Relationship between pharmacokinetics (PK) and pharmacodynamics (PD) Analysis of the relationship between PK and PD made it possible to establish that the decrease in heart rate is almost in direct proportion to the increase in the concentration of ivabradine and S 18982 in the blood plasma when taken in doses of up to 15? 20 mg twice daily. At higher doses, the decrease in heart rate is not proportional to the concentration of ivabradine in the blood plasma and is characterized by a tendency to reach a “plateau”. High concentrations of ivabradine, which can be achieved when used concomitantly with strong CYP3A4 inhibitors, can lead to a pronounced decrease in heart rate, but this risk is lower when combined with moderate CYP3A4 inhibitors (see section "Contraindications", "Precautions" and "Interaction with other medicines"). The PK/PD relationship of ivabradine in pediatric patients aged 6 months to 18 years with chronic heart failure is similar to the PK/PD relationship described in adults.

Indications for use

Symptomatic treatment of chronic stable angina pectoris Raen® is indicated for the symptomatic treatment of chronic stable angina pectoris in adult patients with coronary heart disease (CHD) with normal sinus rhythm and heart rate? 70 beats per minute (bpm). Raenom® is indicated for: ? adult patients with intolerance or contraindications to the use of beta-blockers; ? or in combination with beta-blockers in patients with inadequate control of symptoms of stable angina on the background of the optimal dose of beta-blocker. Treatment of chronic heart failure Raen® is indicated for chronic heart failure II? IV functional classes according to NYHA (New York Heart Association) for patients with systolic dysfunction and sinus rhythm at heart rate ? 75 beats/min in combination with standard therapy, including beta-blocker therapy, or in case of intolerance or contraindications to beta-blocker therapy.

Contraindications

? Hypersensitivity to the active substance or any excipient (see section "Composition")? Resting heart rate below 70 beats per minute before treatment? Cardiogenic shock? Acute myocardial infarction? Severe arterial hypotension (BP

Use during pregnancy and lactation

? Pregnancy, breastfeeding, as well as use in women of reproductive age who do not use reliable methods of contraception (see section “Use during pregnancy and breastfeeding”) Use during pregnancy and breastfeeding Women of reproductive age Women of reproductive age should use reliable methods of contraception during treatment with Raen® (see section “Contraindications”). Pregnancy There are insufficient or no data on the use of ivabradine in women during pregnancy. Animal studies indicate reproductive toxicity. These studies revealed embryotoxic and teratogenic effects. The potential risk for human use is unknown, therefore taking Raenom® during pregnancy is contraindicated (see section "Contraindications"). Breastfeeding Animal experiments show that ivabradine passes into breast milk. Therefore, taking Raenom® is contraindicated during breastfeeding (see section “Contraindications”). Women who require treatment with ivabradine should stop breastfeeding and choose another way to feed their baby. Fertility Studies in rats have shown no effects in either males or females.

Directions for use and doses

Directions for use The tablets must be taken orally twice a day, i.e. once in the morning and once in the evening during meals. Doses Symptomatic treatment of chronic stable angina It is recommended that the decision to initiate treatment or dose titration be made with regular heart rate measurements, ECG or 24-hour ambulatory monitoring. The initial dose of Raenom® should not exceed 5 mg twice daily in patients under 75 years of age. After 3? 4 weeks of treatment, if the patient still has clinical manifestations of stable angina, if the initial dose is well tolerated and the resting heart rate remains stable above 60 beats/min, the dose can be increased to the next higher dose in patients receiving 2.5 mg two once daily or 5 mg twice daily. The maintenance dose should not exceed 7.5 mg twice daily. If, after starting therapy, symptoms of angina persist for 3 months, treatment with Raen® should be discontinued. In addition, discontinuation of treatment with Raen should be considered in the event of a minor symptomatic response in the absence of a clinically significant decrease in resting heart rate within 3 months. If during treatment the resting heart rate decreases to less than 50 beats/min or the patient experiences symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), the dose should be reduced to the minimum effective dose of 2.5 mg twice a day. day (1/2 tablet 5 mg twice a day). After reducing the dose, it is necessary to continue monitoring heart rate (see section "Precautions"). If, despite a dose reduction, the heart rate remains less than 50 beats/min or symptoms of bradycardia persist, treatment with Raen® should be discontinued. Treatment of chronic heart failure (CHF) Treatment should be started only in patients with stable CHF. It is recommended that the attending physician have experience in the treatment of CHF. The usual recommended starting dose of Raenom® is 5 mg twice daily. After two weeks of treatment, the dose may be increased to 7.5 mg twice daily if resting heart rate is consistently greater than 60 beats/min, or may be reduced to 2.5 mg twice daily (1/2 5 mg tablet twice daily) if resting heart rate is consistently less than 50 beats/min or if symptoms associated with bradycardia such as dizziness, fatigue, or hypotension occur. If the heart rate is between 50 and 60 beats/min, the dose should be maintained at 5 mg twice daily. If during treatment the resting heart rate is consistently less than 50 beats/min or the patient experiences symptoms associated with bradycardia, in patients receiving 7.5 mg twice daily or 5 mg twice daily, the dose should be reduced to the next lower doses. If the resting heart rate is consistently greater than 60 beats/min, patients receiving 2.5 mg twice daily or 5 mg twice daily can increase the dose to the next higher dose. Treatment should be discontinued if heart rate remains less than 50 beats/min or symptoms of bradycardia persist (see section "Precautions"). Special Patient Populations Elderly Patients In patients aged 75 years and above, a lower starting dose (2.5 mg twice daily, i.e. 1/2 5 mg tablet twice daily) should be considered before than you will need to increase the dose. Patients with impaired renal function In patients with renal failure and creatinine clearance above 15 ml/min, no dose adjustment is required (see section "Pharmacokinetics"). Data for patients with creatinine clearance below 15 ml/min are not available. Therefore, ivabradine should be used with caution in such patients. Patients with impaired liver function No dose adjustment is required in patients with mild hepatic impairment. Caution should be exercised when using the drug Raenom® in patients with moderate liver failure. Raenom® is contraindicated for use in patients with severe hepatic impairment, since studies of the drug have not been conducted in this population and a significant increase in systemic exposure is expected (see sections “Contraindications” and “Pharmacokinetics”). Pediatric Population The safety and effectiveness of ivabradine in the treatment of chronic heart failure in children under 18 years of age have not been established. Available data are presented in the “Pharmacokinetics” section, but it is not possible to formulate dosage recommendations.

Side effect

The most common side effects of ivabradine, the phenomenon of changes in light perception (phosphenes) and bradycardia, were dose-dependent and were due to the mechanism of its pharmacological action. During clinical studies, the following adverse reactions were reported, the assessment of which is based on the following frequency of occurrence: very often (? 1/10), often (? 1/100 to

Overdose

Symptoms Overdose can lead to severe and prolonged bradycardia. Treatment Treatment of severe bradycardia should be symptomatic and carried out in specialized departments. In case of development of bradycardia in combination with hemodynamic disturbances, symptomatic treatment with intravenous administration of beta-adrenergic agonists, such as isoprenaline, is indicated. If necessary, an artificial pacemaker can be installed.

Interaction with other drugs

Pharmacodynamic interactions Concomitant use with drugs that prolong the QT interval is not recommended, such as: antiarrhythmic drugs that prolong the QT interval (for example, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone); ? Non-antiarrhythmic drugs that prolong the QT interval (eg, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin). The simultaneous use of ivabradine with antiarrhythmic drugs and non-antiarrhythmic drugs that prolong the QT interval should be avoided, as a decrease in heart rate may cause further prolongation of the QT interval. If it is necessary to use such a combination, careful monitoring of cardiac function should be carried out (see section "Precautions"). Cautions for simultaneous use of potassium-sparing diuretics (thiazide diuretics and loop diuretics): hypokalemia may increase the risk of 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. Pharmacokinetic interactions Cytochrome P450 3A4 (CYP3A4) Ivabradine is metabolized with the participation of the cytochrome isoenzyme CYP3A4. In addition, the drug is a very weak inhibitor of this cytochrome. Ivabradine has been shown to have no effect on the metabolism and plasma concentrations of other CYP3A4 substrates (weak, moderate and strong inhibitors). Inhibitors and inducers of the CYP3A4 isoenzyme may interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetics. In drug interaction studies, it was found that inhibitors of the CYP3A4 isoenzyme increase the concentration of ivabradine in the blood plasma, and inducers? lead to its decrease. An increase in the concentration of ivabradine in the blood plasma may be associated with a risk of developing severe bradycardia (see section "Precautions"). Contraindications for simultaneous use: Concomitant use with potent inhibitors of the CYP3A4 isoenzyme, such as antifungals of the azole group (ketoconazole, itraconazole); antibiotics from the macrolide group (clarithromycin, erythromycin for oral administration, josamycin, telithromycin); HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone are contraindicated (see section “Contraindications”). Potent inhibitors of the CYP3A4 isoenzyme? ketoconazole (200 mg once daily) or josamycin (1 g twice daily)? increased the average concentrations of ivabradine in blood plasma by 7? 8 times. Moderate inhibitors of the CYP3A4 isoenzyme: special interaction studies conducted in healthy volunteers and patients showed that the use of ivabradine in combination with drugs that reduce heart rate, diltiazem or verapamil, was accompanied by an increase in the plasma concentration of ivabradine (increase in the area under the concentration-time curve "(AUC) 2 × 3 times), as well as an additional decrease in heart rate by 5 beats/min. The use of ivabradine in combination with these drugs is contraindicated (see section "Contraindications"). Concomitant use of grapefruit juice is not recommended: the concentration of ivabradine in the blood plasma increases immediately after simultaneous administration with grapefruit juice. During therapy with Raen®, you should avoid drinking grapefruit juice. Precautions for simultaneous use Moderate CYP3A4 inhibitors: Concomitant use of ivabradine with other moderate CYP3A4 inhibitors (eg, fluconazole) may be considered if the resting heart rate is more than 70 beats/min. Recommended starting dose of ivabradine? 2.5 mg twice a day, heart rate monitoring is necessary. CYP3A4 inducers: CYP3A4 inducers (eg, rifampicin, barbiturates, phenytoin, Hypericum perforatum

St. John's wort

) may lead to decreased plasma concentrations and decreased activity of ivabradine. Concomitant use of drugs that induce the CYP3A4 isoenzyme may require dose adjustment of ivabradine. When ivabradine was used at a dose of 10 mg twice daily in combination with St. John's wort, a twofold decrease in the AUC of ivabradine was noted. St. John's wort should be limited during treatment with ivabradine. Combined use with other drugs Based on the results of special drug-drug interaction studies, the following drugs do not have a clinically significant effect on the pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (simvastatin ), calcium channel blockers of the dihydropyridine group (amlodipine, lacidipine), digoxin and warfarin. In addition, it was found that ivabradine does not have a clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin and the pharmacodynamics of aspirin. In the main phase III clinical trials, the following drugs were routinely used in combination with ivabradine, which was not accompanied by a change in the safety profile of the therapy: angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics, aldosterone antagonists, short-acting and long-acting nitrates actions, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral hypoglycemic agents, aspirin and other antiplatelet agents. Pediatric Population Interaction studies were conducted in adults only.

Precautionary measures

No effect on clinical outcomes in patients with symptomatic chronic stable angina Raenom® is indicated only for the symptomatic treatment of chronic stable angina as it does not have a beneficial effect on cardiovascular outcomes (eg, myocardial infarction or cardiovascular mortality). Heart Rate Monitoring Taking into account the variability of heart rate throughout the day, periodic heart rate measurements, ECG or 24-hour monitoring should be considered to determine resting heart rate before starting treatment with Raen®, as well as in patients receiving treatment with ivabradine when necessary. dose titration. This also applies to patients with low heart rate, in particular when the heart rate is less than 50 beats/min, or when the dose is reduced (see section "Dosage and Administration"). Heart rhythm disturbances Raenom® is not effective for the treatment or prevention of arrhythmias. There is a high probability of a decrease in its effectiveness due to the development of tachyarrhythmia (for example, ventricular or supraventricular tachycardia). Therefore, Raenom® is not recommended for patients with atrial fibrillation or other types of cardiac arrhythmias associated with sinus node function. Patients receiving treatment with Raen® have an increased risk of developing atrial fibrillation. Atrial fibrillation was more common among patients who were taking amiodarone or class I antiarrhythmic drugs concomitantly with ivabradine. It is recommended to conduct regular clinical monitoring of patients receiving treatment with Raen® for the detection of atrial fibrillation (persistent or paroxysmal), which, if clinically indicated, should also include ECG monitoring (for example, in the case of worsening angina, palpitations, irregular pulse). Patients should be informed about the signs and symptoms of atrial fibrillation and should be advised to seek medical attention if such symptoms occur. If atrial fibrillation occurs during therapy, it is necessary to assess the benefit-risk ratio of further treatment with Raen®. Patients with CHF and intraventricular conduction disorders (left bundle branch block, right bundle branch block) and ventricular dyssynchrony should be closely monitored. Second degree AV blockade It is not recommended to prescribe Raenom® to patients with second degree AV blockade. Use in patients with bradycardia Raen® should not be prescribed to patients if, before starting therapy, the resting heart rate is less than 70 beats/min (see section “Contraindications”). If during therapy the resting heart rate decreases to values less than 50 beats/min or the patient experiences symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), it is necessary to reduce the dose of the drug. If, when the dose of the drug is reduced, the heart rate remains less than 50 beats/min or symptoms of bradycardia persist, the drug should be discontinued (see section “Dosage and Administration”). Combination therapy with calcium channel blockers The use of Raenom® in combination with calcium channel blockers (CCBs) that reduce heart rate, such as verapamil or diltiazem, is contraindicated (see section “Contraindications” and “Interaction with other drugs”). When using the drug Raenom® in combination with nitrates and dihydropyridine CCBs, such as amlodipine, no changes in the safety profile were noted. It has not been established that simultaneous use with CCBs increases the effectiveness of ivabradine. Chronic heart failure The use of Raenom® should be considered only in cases of stable CHF. Caution should be exercised when using the drug Raenom® in patients with NYHA functional class IV CHF due to limited data on the use of the drug in this group of patients. Stroke It is not recommended to use the drug Raenom® immediately after a stroke, since there are no data on the use of the drug in such situations. Functions of visual perception Ivabradine affects the function of the retina. There is no evidence that ivabradine treatment causes long-term retinal toxicity. If visual impairments not described in these instructions occur, you should consider stopping the drug. Caution should be exercised when prescribing Raenom® to patients with retinal pigmentary degeneration. Arterial hypotension There is insufficient data on use in patients with mild or moderate arterial hypotension, therefore caution should be exercised when prescribing Raenom® to such patients. Raenom® is contraindicated in patients with severe arterial hypotension (BP

Raenom 5mg 56 pcs. film-coated tablets

pharmachologic effect

An antianginal drug that slows the heart rate.
The mechanism of action of ivabradine 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 intra-atrial, atrioventricular and intraventricular pathways, as well as on myocardial contractility and ventricular repolarization.

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

Under provoking circumstances (for example, a sharp change in light intensity in the visual field), partial inhibition of Ih channels by ivabradine leads to 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.

The main pharmacological effect of ivabradine is a dose-dependent decrease in 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 2 times a day and revealed a tendency to achieve a plateau effect (no increase in the therapeutic effect with a further increase in the dose of the drug), which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min).

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 treatment. Efficacy was also confirmed for a dose of 7.5 mg 2 times a day. An additional effect when increasing the dose from 5 mg to 7.5 mg 2 times / day was established in a comparative study with atenolol. The time for performing physical activity increased by approximately 1 min after 1 month of using ivabradine at a dose of 5 mg 2 times a day, while after an additional 3-month course of using ivabradine orally at a dose of 7.5 mg 2 times a day, a further increase in this indicator by 25 seconds was noted . The antianginal and anti-ischemic activity of ivabradine has also been 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 noted 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 by 1 mm ) and was 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 studies of the clinical effectiveness of ivabradine, its therapeutic effect was fully maintained for 3-4 months of therapy. There were no signs of decreased effectiveness during treatment, and no withdrawal syndrome was observed after cessation of treatment. The antianginal and anti-ischemic effects of ivabradine were associated with both a dose-dependent decrease in heart rate and a significant decrease in the work product (heart rate x systolic blood pressure) both at rest and during exercise. The effect on blood pressure and peripheral vascular resistance was minor and clinically insignificant.

A sustained decrease in heart rate was observed in patients who took 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 population.

There were no differences between the groups of patients taking ivabradine against the background of standard therapy, and in patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers and placebo, in the total incidence of deaths from cardiovascular diseases diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or worsening of chronic heart failure (CHF) and in the subgroup of patients with a heart rate of at least 70 beats/min.

In patients with exertional angina, the use of ivabradine showed 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 worsening 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 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 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 reduction in the frequency of hospitalizations due to worsening CHF). by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months after the start of ivabradine therapy.

Patients with symptoms of CHF in sinus rhythm and with a heart rate of at least 70 beats/min received standard therapy, which included beta-blockers (89%), 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.

Composition and release form Raenom 5 mg 56 pcs. film-coated tablets

Tablets - 1 tablet:

Active substance: ivabradine hydrobromide 5.863 mg, which corresponds to the content of ivabradine 5 mg;
Excipients: lactose - 44.607 mg, mannitol - 44.53 mg, maltodextrin - 3 mg, croscarmellose sodium - 1 mg, colloidal silicon dioxide - 0.5 mg, magnesium stearate - 0.5 mg;
shell: Opadry pink - 3 mg (polyvinyl alcohol - 1.05 mg, talc - 0.716 mg, titanium dioxide - 0.705 mg, macrogol-3350 - 0.36 mg, methacrylic acid copolymer (type C) - 0.12 mg, iron dye yellow oxide - 0.038 mg , red iron oxide dye - 0.007 mg, sodium bicarbonate - 0.004 mg).

14 pcs. — contour cell packaging (4) — cardboard packs.

Description of the dosage form

Light orange film-coated tablets, oval, biconvex, with two V-shaped scoring lines on the sides, with “CK3” engraved on one side; On a cross section, the core of the tablet is white.

Directions for use and doses

For stable angina, the recommended initial dose of the drug is 10 mg/day (1 tablet 5 mg 2 times/day) for patients under 75 years of age. After 3-4 weeks of using the drug, depending on the therapeutic effect, the daily dose can be increased to 15 mg (1 tablet of 7.5 mg 2 times a day).

If, during therapy with Raen, the resting heart rate decreases to values less than 50 beats/min or the patient experiences symptoms associated with bradycardia (such as dizziness, fatigue or a marked decrease in blood pressure), the dose of Raen should be reduced (for example, to 2.5 mg (1/2 tablet 5 mg) 2 times/day). If, when the dose of the drug is reduced, the heart rate remains less than 50 beats/min or symptoms of severe bradycardia persist, taking the drug Raen should be discontinued.

If, during therapy, symptoms of angina persist for 3 months, treatment with the drug must be discontinued.

For chronic heart failure, the recommended initial dose of Raenom is 10 mg/day (1 tablet 5 mg 2 times/day) for patients under 75 years of age. Treatment should only be started in patients with stable CHF. After 2 weeks of use, the daily dose of Raenom can be increased to 15 mg (1 tablet 7.5 mg 2 times a day) if the heart rate at rest is consistently more than 60 beats/min.

If the heart rate is stable no more than 50 beats/min or if symptoms of bradycardia appear, such as dizziness, fatigue or arterial hypotension, the dose can be reduced to 2.5 mg (1/2 tablet 5 mg) 2 times / day .

If the heart rate is in the range from 50 to 60 beats/min, it is recommended to use the drug Raenom at a dose of 5 mg 2 times a day.

If during therapy the heart rate at rest is consistently less than 50 beats/min or if the patient has symptoms of severe bradycardia, for patients taking the drug at a dose of 5 mg 2 times / day or 7.5 mg 2 times / day, the dose of the drug should be reduced.

If in patients receiving the drug Raenom at a dose of 2.5 mg (1/2 tablet of 5 mg) 2 times / day or 5 mg 2 times / day, the resting heart rate is consistently more than 60 beats / min, the dose of the drug can be increased .

If the heart rate is not more than 50 beats/min or the patient continues to have symptoms of bradycardia, use of the drug Raenom should be discontinued.

For patients aged 75 years and older, the recommended initial dose of the drug is 2.5 mg (1/2 tablet of 5 mg) 2 times a day. In the future, it is possible to increase the dose of the drug.

In patients with impaired renal function with CC more than 15 ml/min, the recommended initial dose of the drug is 10 mg/day (1 tablet 5 mg 2 times/day). After 3-4 weeks of using the drug, depending on the therapeutic effect, the daily dose can be increased to 15 mg (1 tablet 7.5 mg 2 times a day). In patients with CC less than 15 ml/min, the drug should be used with caution (due to insufficient clinical data).

Patients with mild liver failure (up to 7 points on the Child-Pugh scale) are recommended to prescribe Raenom at the usual dose. The recommended initial dose of the drug is 10 mg/day (1 tablet 5 mg 2 times/day). After 3-4 weeks of using the drug, depending on the therapeutic effect, the daily dose can be increased to 15 mg (1 tablet 7.5 mg 2 times a day). Caution should be exercised when using the drug Raenom in patients with moderate liver failure (7-9 points on the Child-Pugh scale). The drug Raenom is contraindicated in patients with severe liver failure (more than 9 points on the Child-Pugh scale), since there is no data on the use of ivabradine in this group of patients (a significant increase in the concentration of ivabradine in the blood plasma can be expected).

The drug is taken orally, morning and evening, during meals.

The decision to initiate therapy and titrate doses must be made with regular monitoring of heart rate and ECG.

Pharmacokinetics

Ivabradine is an S-enantiomer with no signs of bioconversion (according to in vivo studies). The main active metabolite is the N-desmethylated derivative of ivabradine.

Suction.

After oral administration, ivabradine is quickly and almost completely absorbed from the gastrointestinal tract. Cmax in blood plasma is achieved within 1 hour after oral administration on an empty stomach. Bioavailability is approximately 40% due to the “first pass” effect through the liver. Eating increases the absorption time by approximately 1 hour and increases the plasma concentration from 20% to 30%. To reduce the variability of concentration, it is recommended to take the drug simultaneously with meals.

Distribution.

Plasma protein binding is approximately 70%. Vd in equilibrium is about 100 l. Cmax in blood plasma with long-term use at the recommended dose of 5 mg 2 times a day is approximately 22 ng/ml (coefficient of variation = 29%). The average Css in blood plasma is 10 ng/ml (coefficient of variation = 38%).

The pharmacokinetics of ivabradine is linear over the dose range from 0.5 to 24 mg.

Metabolism.

Ivabradine is predominantly metabolized in the liver and intestines by oxidation involving the CYP3A4 isoenzyme. The main active metabolite is the N-desmethylated derivative (S 18982), which accounts for 40% of the ivabradine dose. Metabolism of the active metabolite ivabradine also involves the CYP3A4 isoenzyme. Ivabradine has low affinity for the CYP3A4 isoenzyme and does not induce or inhibit it. In this regard, it is unlikely that ivabradine affects the metabolism or concentration of CYP3A4 isoenzyme substrates in blood plasma. At the same time, simultaneous use of ivabradine with potent inhibitors or inducers of cytochrome P450 can significantly affect the concentration of ivabradine in the blood plasma.

Excretion.

T1/2 of ivabradine is, on average, 2 hours (70-75% AUC), effective T1/2 is 11 hours. Total clearance is approximately 400 ml/min, renal clearance is about 70 ml/min. Metabolites are excreted at the same rate through the kidneys and intestines. About 4% of the dose taken is excreted unchanged by the kidneys.

Pharmacokinetics in special groups of patients.

Pharmacokinetic parameters (AUC and Cmax) do not differ significantly in groups of patients aged 65 years and older, 75 years and older, and the general patient population.

The effect of renal failure (creatinine clearance from 15 to 60 ml/min) on the kinetics of ivabradine is minimal, because only about 20% of ivabradine and its active metabolite S 18982 is excreted by the kidneys.

In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale), the AUC of free ivabradine and its active metabolite is 20% greater than in patients with normal liver function. Data on the use of ivabradine in patients with moderate liver failure (7-9 points on the Child-Pugh scale) are limited and do not allow us to evaluate the pharmacokinetics of the drug in this group of patients. There are currently no data on the use of ivabradine in patients with severe hepatic impairment (Child-Pugh score greater than 9).

The relationship between pharmacokinetic and pharmacodynamic properties.

Analysis of the relationship between the pharmacokinetic and pharmacodynamic properties of ivabradine made it possible to establish that the decrease in heart rate is directly proportional to the increase in the concentration of ivabradine and the active metabolite S18982 in the blood plasma when used in doses of up to 15-20 mg 2 times a day. At higher doses of the drug, the slowing of heart rate is not proportional to the concentration of ivabradine in the blood plasma and is characterized by a tendency to reach a plateau. High concentrations of ivabradine, which can be achieved when used simultaneously with strong inhibitors of the CYP3A4 isoenzyme, can lead to a pronounced decrease in heart rate, but this risk is lower when combined with moderate inhibitors of the CYP3A4 isoenzyme.

Indications for use Raenom 5mg 56 pcs. film-coated tablets

Stable angina.

Treatment of stable angina in patients with normal sinus rhythm:

If you are intolerant or have contraindications to the use of beta-blockers;
in combination with beta-blockers with inadequate control of symptoms of stable angina pectoris against the background of the optimal dose of beta-blocker.

Chronic heart failure:

To reduce the incidence of cardiovascular complications (mortality from cardiovascular diseases and hospitalization due to worsening CHF) in patients with chronic heart failure, with sinus rhythm and heart rate of at least 70 beats/min.

Contraindications

Hypersensitivity to ivabradine or any of the auxiliary components of the drug;
bradycardia (heart rate at rest less than 60 beats/min (before treatment));
cardiogenic shock;
acute myocardial infarction;
severe arterial hypotension (systolic blood pressure less than 90 mm Hg and diastolic blood pressure less than 50 mm Hg);
severe liver failure (more than 9 points on the Child-Pugh scale);
sSSU;
sinoatrial block;
presence of an artificial pacemaker;
unstable angina;
AV block of the third degree;
simultaneous use with powerful 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;
simultaneous use with slow calcium channel blockers (SCBCs) that reduce heart rate, such as verapamil or diltiazem;
lactase deficiency, lactose intolerance, glucose/galactose malabsorption syndrome.

The drug should be prescribed with caution for moderate liver failure (less than 9 points on the Child-Pugh scale); severe renal failure (creatinine clearance less than 15 ml/min); congenital prolongation of the QT interval; simultaneous use of drugs that prolong the QT interval; simultaneous use of moderate inhibitors and inducers of CYP3A4 and grapefruit juice; simultaneous use with potassium-sparing diuretics; asymptomatic left ventricular dysfunction; AV blockade of the second degree; recent stroke; CHF functional class IV according to the NYHA classification; pigmentary degeneration of the retina (retinitis pigmentosa); arterial hypotension; patients over 75 years of age.

Application of Raenom 5 mg 56 pcs. film-coated tablets during pregnancy and breastfeeding

The use of the drug Raenom is contraindicated during pregnancy. There is currently insufficient data on the use of ivabradine during pregnancy. Preclinical studies of ivabradine revealed embryotoxic and teratogenic effects.

Women of reproductive age should use reliable methods of contraception during treatment with Raen.

The use of the drug Raenom is contraindicated during breastfeeding. There is no information on the excretion of ivabradine in breast milk. In animal studies, ivabradine has been shown to be excreted in breast milk.

The use of the drug is contraindicated in people under the age of 18 (the effectiveness and safety in this age group have not been studied).

special instructions

Heart rhythm disturbance.

Ivabradine is not effective for the treatment or prevention of arrhythmias. Its effectiveness decreases against the background of the development of tachyarrhythmia (for example, ventricular or supraventricular tachycardia). Raenom is not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function.

During therapy with Raen, patients should be clinically monitored to detect atrial fibrillation (paroxysmal or permanent). If clinically indicated (eg, worsening angina, palpitations, irregular heart rhythm), an ECG should be included in routine monitoring.

The risk of developing atrial fibrillation may be higher in patients with CHF taking the drug Raenom. Atrial fibrillation was more common among patients who were taking amiodarone or class I antiarrhythmic drugs concomitantly with ivabradine. Patients with CHF and intraventricular conduction disorders (left or right bundle branch block) and ventricular dyssynchrony should be monitored.

Use in patients with bradycardia.

Ivabradine is contraindicated if, before starting therapy, the resting heart rate is less than 60 beats/min. If during therapy the resting heart rate decreases to values less than 50 beats/min or the patient experiences symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), the dose of the drug should be reduced. If, when the dose of the drug is reduced, the heart rate remains less than 50 beats/min or symptoms associated with bradycardia persist, then taking the drug Raen should be discontinued.

Combined use as part of antianginal therapy.

The use of the drug Raenom together with BMCCs that reduce heart rate, such as verapamil or diltiazem, is contraindicated. With the combined use of ivabradine with nitrates and BMCA, dihydropyridine derivatives, such as amlodipine, no changes in the safety profile of the therapy were noted. It has not been established that combined use with BMCC increases the effectiveness of ivabradine.

Stroke.

It is not recommended to prescribe the drug Raenom immediately after a stroke, because There are no data on the use of the drug during this period.

Functions of visual perception.

Ivabradine affects the function of the retina. To date, no toxic effects of ivabradine on the retina have been identified. However, there is no data on the effect of ivabradine on the retina with long-term use (more than 1 year). If visual impairments not described in these instructions occur, you should consider stopping taking the drug Raen. Patients with retinitis pigmentosa should take Raenom with caution.

Arterial hypotension.

Raenom should be prescribed with caution to patients with arterial hypotension (due to insufficient clinical data).

Raenom is contraindicated in severe arterial hypotension (systolic blood pressure less than 90 mm Hg and diastolic blood pressure less than 50 mm Hg).

Atrial fibrillation (atrial fibrillation) - cardiac arrhythmias.

An increase in the risk of developing severe bradycardia with the use of ivabradine during pharmacological cardioversion to restore sinus rhythm has not been proven. However, due to insufficient data, if it is possible to delay planned electrical cardioversion, use of the drug Raen should be stopped 24 hours before it is performed.

Use in patients with congenital long QT syndrome or in patients taking drugs that prolong the QT interval.

Raenom should not be used for congenital long QT syndrome, or in combination with drugs that can prolong the QT interval. If simultaneous use of such drugs is necessary, strict ECG monitoring is necessary. A decrease in heart rate due to the use of the drug Raenom may aggravate the prolongation of the QT interval, which, in turn, can provoke the development of a severe form of arrhythmia, in particular, polymorphic ventricular tachycardia of the “pirouette” type.

Patients with arterial hypertension who require switching to another antihypertensive drug.

When changing antihypertensive therapy in patients with CHF taking the drug Raenom, blood pressure monitoring is required at appropriate intervals.

Chronic heart failure.

Before deciding on the use of the drug Raenom, the course of heart failure must be stable. Caution should be exercised when using the drug Raenom in patients with CHF functional class IV according to the NYHA classification due to limited data on the use of the drug in this category of patients.

Moderate liver failure.

In case of moderately severe liver failure (less than 9 points on the Child-Pugh scale), therapy with Raen should be carried out with caution.

Severe renal failure.

In case of severe renal failure (creatinine clearance less than 15 ml/min), therapy with Raen should be carried out with caution.

Excipients.

Raenom contains lactose and is therefore not recommended for patients with lactase deficiency, lactose intolerance and glucose/galactose malabsorption syndrome.

Impact on the ability to drive vehicles and machinery.

Ivabradine does not affect the ability to drive vehicles or perform work requiring a high speed of psychomotor reactions. However, one should remember about the possibility of photopsia occurring with a sharp change in lighting intensity, especially when driving at night.

Overdose

Symptoms: An overdose of ivabradine can lead to severe and prolonged bradycardia.

Treatment: therapy for severe bradycardia is symptomatic, carried out in specialized departments. In case of development of bradycardia in combination with hemodynamic disturbances, symptomatic treatment with intravenous administration of beta-adrenergic agonists, such as isoprenaline, is indicated. If necessary, an artificial pacemaker can be installed.

Side effects Raenom 5 mg 56 pcs. film-coated tablets

From the senses: very often - changes in light perception (photopsia); often - blurred vision; infrequently - vertigo; unspecified frequency - diplopia, visual impairment.

From the cardiovascular system: often - bradycardia, AV block of the first degree, ventricular extrasystole, short-term increase in blood pressure; infrequently - palpitations, supraventricular extrasystole; very rarely - atrial fibrillation, AV block of II and III degrees, SSSU; unspecified frequency - a pronounced decrease in blood pressure, possibly associated with bradycardia.

From the digestive system: infrequently - nausea, constipation, diarrhea.

From the side of the central nervous system: often - headache (especially in the first month of therapy), dizziness, possibly associated with bradycardia; unspecified frequency - fainting, possibly associated with bradycardia.

From the respiratory system: infrequently - shortness of breath.

Drug interactions

Undesirable combinations.

Drugs that prolong the QT interval:

Antiarrhythmic drugs that prolong the QT interval (for example, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone);
drugs that prolong the QT interval that are not antiarrhythmic drugs (for example, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for intravenous administration).

The simultaneous use of ivabradine and these drugs should be avoided, since a decrease in heart rate may cause further prolongation of the QT interval. If simultaneous use of these drugs is necessary, ECG readings should be carefully monitored.

Isoenzyme CYP3A4.

Ivabradine is metabolized in the liver with the participation of the CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. Ivabradine does not have a significant effect on the metabolism and plasma concentrations of other substrates (strong, moderate and weak inhibitors) of the CYP3A4 isoenzyme. 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 the concentration of ivabradine in the blood plasma.

Increasing the concentration of ivabradine in blood plasma may increase the risk of developing severe bradycardia.

Contraindicated combinations.

Potent inhibitors of the CYP3A4 isoenzyme.

Concomitant use of ivabradine with potent 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 are contraindicated. Potent inhibitors of the CYP3A4 isoenzyme - ketoconazole (200 mg 1 time / day) or josamycin (1 g 2 times / day) - increase the average concentration of ivabradine in the blood plasma by 7-8 times.

Moderate inhibitors of the CYP3A4 isoenzyme.

The simultaneous use of ivabradine and diltiazem or verapamil (drugs that slow heart rate) in healthy volunteers and patients was accompanied by an increase in ivabradine AUC by 2-3 times and an additional decrease in heart rate by 5 beats/min. The use of these combinations is contraindicated.

Combinations requiring caution.

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.

Concomitant use with inducers of the CYP3A4 isoenzyme, such as rifampicin, barbiturates, phenytoin and herbal remedies containing St. John's wort (Hypericum perforatum), may lead to a decrease in the plasma concentration and activity of ivabradine and require the selection of a higher dose of ivabradine. With the combined use of ivabradine and preparations containing St. John's wort, a twofold decrease in the AUC of ivabradine was noted. During therapy with Raen, you should, if possible, avoid the use of drugs and products containing St. John's wort.

The drug should be used with caution simultaneously with potassium-sparing diuretics (diuretics of the thiazide group 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.

Combined use with other drugs.

The absence of a clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine has been shown with the simultaneous use of the following drugs: proton pump inhibitors (omeprazole, lansoprazole), PDE5 inhibitors (for example, sildenafil), HMG-CoA reductase inhibitors (for example, simvastatin), BMCC - dihydropyridine derivatives series (for example, amlodipine, lacidipine), digoxin and warfarin. It has been shown that ivabradine does not have a clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin and the pharmacodynamics of acetylsalicylic acid.

Ivabradine has been used in combination with ACE inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics, aldosterone antagonists, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral hypoglycemic agents, acetylsalicylic acid and other antiplatelet drugs. The use of the above drugs was not accompanied by a change in the safety profile of the therapy.

Other interactions requiring caution when used together.

When taking grapefruit juice, there was a twofold increase in the concentration of ivabradine in the blood plasma. During therapy with Raen, you should avoid drinking grapefruit juice if possible.

Ryan

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.

The main pharmacological effect of ivabradine is a dose-dependent decrease in 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 2 times a day and revealed a tendency to achieve a plateau effect (no increase in the therapeutic effect with a further increase in the dose of the drug), which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min).

A sustained decrease in heart rate was observed in patients who took 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 population.

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 reduction in the frequency of hospitalizations due to worsening CHF ) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed 3 months after the start of ivabradine therapy.

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

Pharmacokinetics

Ivabradine is an S-enantiomer with no signs of bioconversion (according to in vivo studies). The main active metabolite is the N-desmethylated derivative of ivabradine.

Suction

Distribution

The pharmacokinetics of ivabradine is linear over the dose range from 0.5 to 24 mg.

Metabolism

Removal

Pharmacokinetics in special groups of patients

Pharmacokinetic parameters (AUC and Cmax) do not differ significantly in groups of patients aged 65 years and older, 75 years and older, and the general patient population.

Relationship between pharmacokinetic and pharmacodynamic properties

Analysis of the relationship between the pharmacokinetic and pharmacodynamic properties of ivabradine made it possible to establish that the decrease in heart rate is directly proportional to the increase in the concentration of ivabradine and the active metabolite S 18982 in the blood plasma when used in doses of up to 15-20 mg 2 times a day. At higher doses of the drug, the slowing of heart rate is not proportional to the concentration of ivabradine in the blood plasma and is characterized by a tendency to reach a plateau. High concentrations of ivabradine, which can be achieved when used simultaneously with strong inhibitors of the CYP3A4 isoenzyme, can lead to a pronounced decrease in heart rate, but this risk is lower when combined with moderate inhibitors of the CYP3A4 isoenzyme.