Raenom, 7.5 mg 56 pcs.

Ivabradine is a drug that slows the heart rhythm. The mechanism of action of ivabradine is selective and specific inhibition of If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate (HR).

Ivabradine has a selective effect on the sinus node without affecting pulse conduction time along the atrial, atrial-ventricular and intraventricular conduction pathways and on myocardial contractility and ventricular repolarization. Ivabradine can also interact with Ih, retinal channels similar in structure to //channels of the heart. They are involved in the mechanisms of temporal adaptation of the visual perception system by changing the retinal response to bright light stimuli.

In provoking circumstances (e.g., a sharp change in light intensity in the visual field area), partial inhibition of If channels by ivabradine results in 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 ivabradia is a dose-dependent decrease in heart rate. The dose-dependent HR decrease has been analyzed by gradually increasing the dose of ivabradia up to 20 mg twice daily and shows the tendency to reach a “plateau” effect (no increase of therapy effect with further increase of the dose), which reduces the risk of bradycardia (HR <40 bpm) (see section "Adverse drug effect").

In using the drug in the recommended doses, the degree of HR reduction depends on its initial value and is about 10-15 bpm at rest and during physical activity, as a result of which the heart rate and myocardial oxygen demand decrease. Ivabradine has no effect on vitric conduction, myocardial contractility (no negative inotron effect) and the process of ventricular repolarization.

In clinical electrophysiological studies ivabradine had no effect on atrial-ventricular or intraventricular conduction time and corrected QT intervals. In studies in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%) it has been shown that ivabradine has no effect on myocardial contractility. It was found that ivabradine at a dose of 5 mg 2 times a day improved the values of stress tests after 3-4 weeks of treatment.

The efficacy was also confirmed for the dose of 7.5 mg 2 times 15 days. An additional effect when the dose was increased from 5 mg to 7.5 mg 2 times a day was established in a comparative study with atepolol. Exercise time increased by about I minute after 1 month of using ivabradine in a dose of 5 mg 2 times a day, and after an additional 3-month course of taking ivabradine in a dose of 7.5 mg 2 times a day orally, a further increase of 25 seconds in this parameter was noted.

The antianginal and anti-ischemic activity of ivabradine was also confirmed in patients aged 65 years and older. The efficacy of ivabradine at the doses of 5 mg and 7.5 mg twice daily was observed in all exercise test parameters (total exercise duration, time to limiting angina attack, time to onset of angina attack and time to ST-segment depression by 1 mm) and was accompanied with reduction of angina attack frequency by approximately 70%.

The use of ivabradine 2 times daily provided consistent therapeutic efficacy for 24 hours. In patients taking ivabradine additional efficacy in all exercise test values was shown when added to the maximum dose of atenolol (50 mg) at the onset of its therapeutic activity (12 hours after oral administration).

The efficacy of ivabradine has not improved when added to the maximum dose of amlodinine at the start of the therapy (12 hours after oral administration), whereas at the peak of amlodinine activity (3-4 hours after oral administration) ivabradine has been demonstrated to be more effective.

In studies of the clinical efficacy of ivabradine its therapeutic effect was fully maintained for 3-4 months of therapy. There were no signs of decreased efficacy during treatment and no “withdrawal” syndrome was observed after discontinuation of treatment. Antianginal and antiischemic effects of ivabradine were associated with both dose-dependent HR reduction and a significant reduction in work product (HR x systolic blood pressure) both at rest and during exercise.

The effects on blood pressure (BP) and total peripheral vascular resistance (TPR) were insignificant and clinically insignificant. Sustained HR slowing was noted in patients who had been 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 population. No differences were found between groups of patients who received ivabradine against standard therapy and patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received bsta-adsnoblockers and placebo, but the total frequency of cardiovascular deaths, hospitalization for acute myocardial infarction, hospitalization for new heart failure or worsening chronic heart failure (CHF), and in a subgroup of patients with a HR of at least 70 bpm.

The use of ivabradine in patients with HR of at least 70 bpm has been shown to reduce the rate of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the rate of revascularization by 30%. In patients with angina pectoris against the background of ivabradine use there was decreased relative risk of complications (rate of cardiovascular deaths, hospitalizations for acute myocardial infarction, hospitalizations for new cases of heart failure or worsening of CHF) by 24%.

The noted therapeutic benefit is achieved primarily through a 42% reduction in the rate of hospitalizations for acute myocardial infarction. The reduction in the rate of hospitalizations for fatal and non-fatal myocardial infarction in patients with HR over 70 bpm is even more significant and reaches 73%.

In general, good tolerability and safety of the drug were noted. Against the background of ivabradine use in patients with CVA II-IV functional class according to NYIIA classification with left ventricular wall thickness less than 35% there was clinically and statistically significant 18% decrease of relative risk of complications (incidence of cardiovascular deaths and decrease of hospitalization rate due to worsening of CVD course). The absolute risk reduction was 4.2%.

A pronounced therapeutic effect was observed after 3 months of starting therapy with ivabradine. The decrease of cardiovascular mortality and the rate of hospitalizations due to worsening of CHF course was observed irrespective of age, sex, functional class of CHF, use of beta-adrenoblockers, ischemic or non-ischemic etiology of CHF, presence of diabetes mellitus or arterial hypertension in anamnesis.

. Patients with symptoms of CVA with sinus rhythm and a HR of at least 70 bpm received standard therapy, which included beta-adrenoblockers (89%), angiotensin-converting enzyme inhibitors (A11F) and/or angiotensin II receptor antagonists (91%), diuretics (83%) and aldosterone antagonists (60%).

The use of ivabradine for 1 year has been shown to prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug. Improvement of NYHA functional class has been shown during ivabradine use. In patients with HR of 80 bpm there was decreased HR by an average of 15 bpm.

Indications

Stable angina pectoris

The therapy of stable angina pectoris in patients with normal sinus rhythm: When bta-adrenoblockers are intolerant or contraindicated; in combination with beta-adsnoblockers when stable angina symptoms are not adequately controlled against the optimal dose of a beta-adrenoblocker.

Chronic heart failure

To reduce the incidence of cardiovascular complications (cardiovascular mortality and hospitalization due to worsening course of CHF) in patients with chronic heart failure, with sinus rhythm and HR of at least 70 bpm.

Active ingredient

Composition

Active substance:

Ivabradine hydrobromide – 8.795 mg (equivalent to ivabradine 7.5 mg).

Auxiliary substances:

Lactose – 41.675 mg,

Mannitol – 44.530 mg,

Maltodextrin -3.000 mg,

croscarmellose sodium – 1,000 mg,

colloidal silicon dioxide – 0.500 mg,

magnesium stearate – 0.500 mg.

Pill coating:

Opadray pink – 3,000 mg (contains: polyvinyl alcohol -1.0.050 mg, talc 0.716 mg, titanium dioxide 0.705 mg, macrogol-3350 0.360 mg, methacrylic acid copolymer (type C) 0.120 mg, iron oxide yellow dye -0.038 mg, iron oxide red dye 0.007 mg, sodium hydrogen carbonate 0.004 mg).

How to take, the dosage

Overly, 2 times a day (morning and evening), with meals.

The initial recommended daily dose is 10 mg per day (5 mg twice daily). Depending on the therapeutic effect, after 3 – 4 weeks the daily dose can be increased up to 15 mg (7.5 mg 2 times a day).

If the HR decreases less than 50/min or bradycardia-related symptoms (dizziness, fatigue, or decreased BP) occur during therapy, a lower dose of the drug should be used.

If the HR does not return to normal when the dose is reduced and remains less than 50/min, the drug should be discontinued.

In elderly patients, treatment should start with an initial dose of 2.5 mg (1/2 tablet of 5 mg) twice daily; the daily dose may be increased depending on the patient’s condition.

Interaction

Unwanted drug combinations Drugs that prolong the QT interval Antiarhythmic drugs that prolong the QT interval (e.g., quipidine, disopyramide, bspridyl, sotalol, ibutilide, amiodarone); Non-antiarrhythmic QT drugs (e.g., pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).

The concomitant use of ivabradine and the above drugs should be avoided because the pacing may cause additional prolongation of the QT interval. ECG readings should be closely monitored if simultaneous use of these drugs is necessary.

Ivabradine is metabolized in the liver via the CYP3A4 isoenzyme of the cytochrome P450 system and is a very weak inhibitor of this cytochrome.

Ivabradine has no significant effect on the metabolism and plasma concentrations of other substrates (potent, moderate and weak inhibitors) of CYP3A4 isoenzyme. At the same time, inhibitors and inducers of CYP3A4 isoenzyme may interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties.

Inhibitors of CYP3A4 enzyme have been found to increase and inducers of CYP3A4 enzyme decrease the plasma concentration of ivabradine.

Contrast drug combinations Concurrent use of ivabradine with potent inhibitors of CYP3A4, such as antifungal agents of azole group (ketocoiazole, itraconazole); Macrolide antibiotics (clarithromycin, oral erythromycin, jozamycin, telithromycin); HIV protease inhibitors (nelfipavir, ritonavir) and nefazodone, contraindicated (see contraindicated (see Contraindications).

Powerful inhibitors of CYP3A4 isoenzyme – ketokoiazole (200 mg once daily) or josamycin (1 g 2 times daily) – increase the average plasma concentrations of ivabradine by 7-8 times. Moderate CYP3A4 isoenzyme inhibitors Concomitant use of ivabradine and diltiazem or verapamil (heart rate-lowering drugs) in healthy volunteers and patients was accompanied by 2-3-fold increase of ivabradine AUC and additional HR reduction by 5 bpm.

The use of these combinations is contraindicated (see section “Contraindications”). Drug combinations requiring caution Moderate CYP3A4 isoenzyme inhibitors. The use of ivabradine in combination with other moderate CYP3A4 isoenzyme inhibitors (e.g., fluconazole) is possible provided that the resting HR is more than 60 bpm. The recommended starting dose of ivabradine is 2.5 mg 2 times daily.

The heart rate should be controlled. Concomitant use with CYP3A4 inducers, such as rifampicin, barbiturates, phenytoin and herbal products containing Hypericum perforatum, may decrease the plasma concentration and activity of ivabradine and require using a higher dose of ivabradine.

When Ivabradine and preparations containing Hypericum perforatum are used together, a twofold decrease in the AUC of Ivabradine has been noted. During the therapy with the drug Raen, if possible, avoid the use of drugs and products containing St. John’s Wort.

Contraindications

Hypersensitivity to ivabradine or any of the excipients of the drug; Bradycardia (resting heart rate less than 60 bpm (before treatment);

Cardiac shock;

Acute myocardial infarction;

Severe arterial hypotension (systolic BP less than 90 mm Hg. BP less than 90 mm Hg and diastolic BP less than 50 mm Hg.);

Hepatic insufficiency (more than 9 points in Child-Puo score);

Application in women of childbearing age who do not use reliable contraceptive methods;

Age less than 18 years (the efficacy and safety of the drug in this age group has not been studied);

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

With caution Moderate hepatic insufficiency (less than 9 points by Child-Puo scale); severe renal insufficiency (CK less than 15 ml/min); congenital prolongation of QT interval (see. section “Interaction with other medicinal products”); concomitant use of drugs that prolong the QT interval; concomitant use of moderate inhibitors and inducers of cytochrome CYP3A4 and grapefruit juice isoenzymes; concomitant use with potassium-bearing diuretics; Asymptomatic left ventricular dysfunction; Grade II atrioventricular block; recent stroke; CHF class IV according to NYHA classification; retinal pigmented degeneration (retinitis pigmentosa), arterial hypotension; older than 75 years.

Side effects

The most frequent adverse effects of ivabradnine, bradycardia and photopsia, were dose-dependent and were due to the mechanism of its pharmacological action.

The undesirable adverse reactions are presented by system-organ class according to the MedDRA classification and with frequency of occurrence: Very common (>1/10); common (>1/100, <1/10); infrequent (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000); frequency unknown – not enough data to estimate frequency of development.

Nervous system disorders Frequent: headache (especially in the first month of therapy), dizziness, possibly associated with bradycardia; Infrequent: vertigo, muscle spasms; Frequent unknown: syncope, possibly associated with bradycardia.

Visual disorders Very common: changes in light vision (photopsia); Often: blurred vision; Often unknown: diplopia, visual disturbances.

Cardiovascular disorders Often: bradycardia, atrioventricular block of degree I, ventricular extrasystole, transient BP increase; Infrequent: palpitation, supraventricular extrasystole, prolongation of QT interval on ECG; Very rare: Atrial fibrillation, atrioventricular (AV) block of P-S degree, sinus node weakness syndrome; Frequent unknown: marked decrease in BP, possibly associated with bradycardia.

The following are the adverse events identified in clinical studies, which occurred with equal frequency in both the group of patients receiving ivabradine and in the control group, which suggests their association with the disease itself and not with taking ivabradine: sinus arrhythmia, angina pectoris, including unstable angina pectoris, atrial fibrillation, myocardial ischemia, myocardial infarction, and ventricular tachycardia.

Respiratory system, thorax and mediastinum disorders

Infrequently: dyspnea.

Gastrointestinal tract disorders

Infrequent: nausea, constipation, diarrhea.

Skin and subcutaneous tissue disorders

Prevalence unknown: skin rash, itching, erythema, angioedema, urticaria.

Muscular and connective tissue disorders

Infrequent: muscle spasms.

Impact on the results of laboratory and instrumental studies Infrequent: hyperuricemia, eosinophilia, increased concentration of creatinine in serum.

General disorders and disorders at the site of administration

Prevalence unknown: asthenia, increased fatigue, malaise, possibly associated with bradycardia.

Similarities