Bravadin pills 5mg, 56pcs

Composition

for 1 tablet of 5 mg/7.5 mg:

Core:

Active ingredient:

Ivabradine hydrobromide 5.864 mg/8.796 mg, which corresponds to ivabradine 5 mg/7.5 mg

Auxiliary substances:

Lactose monohydrate, microcrystalline cellulose, povidone-K 30, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate

Film shell:

Opadray orange 03H325991

1Composition of Orange leaf litter 03H32599:

Hypromellose, titanium dioxide (E171), talc, propylene glycol, iron oxide yellow dye (E172), iron oxide Red dye (e172)

Pharmacological action

antianginal agent

Clinical Pharmacology

Pharmacodynamics

Ivabradine is a drug that slows the heart rate, the mechanism of action of which is to selectively and specifically inhibit the I_-fchannels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate the heart rate (HR). Ivabradine has a selective effect on the sinus node, without affecting the time of impulses along the intra-atrial, atrioventricular and intraventricular pathways, as well as the contractility of the myocardium and ventricular repolarization.

Ivabradine can also_{interact with the}ih channels of the retina of the eye, similar_{to the}If channels of the heart, which are involved in the occurrence of temporary changes in the visual perception system due to changes in the retinal response to bright light stimuli.

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

The main pharmacological feature of ivabradine is the ability of dose-dependent heart rate reduction. The analysis of the dependence of the decrease in heart rate on the dose of ivabradine was carried out with a gradual increase in the dose 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), which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min) (see the section “Side effect”).

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

Ivabradine does not affect intracardiac conduction, myocardial contractility (does not cause a negative inotropic effect) and the process of ventricular repolarization.

In clinical electrophysiological studies, ivabradine did not affect the timing of impulses along the atrioventricular or intraventricular pathways, as well as the corrected QT interval (QTc).

In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] 30-45%), ivabradine has not been shown to affect myocardial contractility.

It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of exercise tests after 3-4 weeks of therapy. The effectiveness was also confirmed for a dose of 7.5 mg 2 times a day. In particular, an additional effect was found when the dose was increased from 5 to 7.5 mg 2 times a day. The anti-anginal and anti-ischemic activity of ivabradine was also confirmed for patients aged 65 years and older. The effectiveness of ivabradine at doses of 5 mg and 7.5 mg 2 times a day was accompanied by a decrease in the frequency 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 efficacy of the drug, the effects of ivabradine were completely preserved during the 3 – and 4-month treatment periods. During treatment, there were no signs of developing tolerance (reduced effectiveness), and after discontinuation of treatment, there was no “withdrawal” syndrome. The anti-anginal and anti-ischemic effects of ivabradine were associated with a dose-dependent reduction in heart rate, as well as with a significant decrease in the work product (heart rate x systolic blood pressure [BP]), both at rest and during exercise. The effect on blood pressure and total peripheral vascular resistance (OPSS) was insignificant and clinically insignificant.

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

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

Against the background of ivabradine use, an improvement in the functional class of CHF according to the NYHA classification was shown.

Patients with a heart rate of 80 beats / min showed a decrease in heart rate by an average of 15 beats/min.

In a randomized placebo-controlled trial involving 97 patients, data from specific ophthalmic studies to assess the function of the cone and rod system, as well as the ascending visual pathway (for example, electroretinogram, static and kinetic perimetry, color vision study, and visual acuity determination) in patients with chronic stable angina treated with ivabradine for more than 3 years, no toxic effects on the retina were detected.

Pharmacokinetics

Ivabradine is an S-enantiomer that shows no biological conversion in invivo studies. The N-desmethylated derivative of ivabradine is the main active metabolite.

Absorption and bioavailability

Ivabradine is rapidly and almost completely absorbed in the gastrointestinal tract after oral use on an empty stomach, reaching its maximum concentration (cmax) in blood plasma after approximately 1 hour. Absolute bioavailability is about 40% and is due to the effect of “primary passage” through the liver.

Food intake increases the time of absorption of ivabradine by approximately 1 hour and increases the concentration in blood plasma from 20 to 30%. It is recommended to take tablets during meals in order to reduce the variability of concentration.

Distribution

Ivabradine binds to plasma proteins by approximately 70%, the volume of distribution in patients at steady state is about 100 liters. _{Cmax of}ivabradine in blood plasma after prolonged oral use of a dose of 5 mg 2 times a day is 22 ng / ml (coefficient of variation (CV) = 29 %). The average steady-state plasma concentration is 10 ng / ml (CV = 38%).

Metabolism

Ivabradine is largely metabolized in the liver and intestines by oxidation by the CYP3A4 isoenzyme. The main active metabolite is the N-desmethylated derivative (S18982) with a concentration of about 40% relative to the concentration of the starting substance. The metabolism of this active metabolite also occurs with the participation of the isoenzyme CYP3A4. Ivabradine has a low degree of affinity for the CYP3A4 isoenzyme, does not demonstrate clinically significant induction or inhibition of the CYP3A4 isoenzyme, so changes in the metabolism or concentration of substrates of the CYP3A4 isoenzyme in blood plasma under the influence of ivabradine are unlikely. On the contrary, potent inhibitors and inducers of the cytochrome P450 system can significantly affect the concentration of ivabradine in blood plasma.

Deduction

The half-life (_half-life) of ivabradine is on average 2 hours (70-75% relative to the area under the concentration-time curve (AUC) in blood plasma), the effective_half – life is 11 hours. Total clearance is about 400 ml / min, renal clearance is about 70 ml / min. Elimination of metabolites occurs equally through the intestines and kidneys. About 4% of the oral dose is excreted unchanged by the kidneys.

Linearity / non-linearity

The pharmacokinetics of ivabradine are linear in the dose range of 0.5-24 mg.

Special patient groups

Elderly and senile patients

Pharmacokinetic parameters (AUC and_cmax) do not differ significantly in elderly patients (≥ 65 years), senile patients (≥ 75 years) and the general patient population.

Impaired renal function

The change in ivabradine kinetics in patients with renal insufficiency (creatinine clearance [CC]15-60 ml / min) is minimal, since only about 20% of ivabradine and its active metabolite s18982 are excreted by the kidneys.

Impaired liver function

In patients with mild hepatic insufficiency (up to 7 points on the Child-Pugh scale), the AUC of ivabradine and its metabolite is 20% higher than in patients with normal liver function. Data on the use of ivabradine in patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale) are limited and do not allow us to conclude about the pharmacokinetics of ivabradine in this group of patients, and in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale) are absent.

Relationship between pharmacokinetic and pharmacodynamic properties

The decrease in heart rate is directly proportional to the increase in plasma concentrations of ivabradine and the active metabolite S 18982 when taken at doses of 15-20 mg 2 times a day. At higher doses of the drug, the decrease in heart rate does not have a proportional dependence on the concentration of ivabradine in blood plasma and is characterized by a tendency to achieve a “plateau”effect. High concentrations of ivabradine in blood plasma, which can be achieved with simultaneous use of ivabradine with powerful inhibitors of the CYP3A4 isoenzyme, can lead to a pronounced decrease in heart rate, but this risk is reduced when used simultaneously with moderate inhibitors of the CYP3A4 isoenzyme.

Indications

Symptomatic treatment of stable angina

Symptomatic treatment of stable angina in ischemic heart disease (CHD) in adult patients with a normal sinus rhythm and heart rate of at least 70 beats/min:

· if they are intolerant or have contraindications to the use of beta-blockers;

· in combination with beta-blockers with inadequate control of stable angina against the background of an optimal dose of beta-blockers.

Treatment of chronic heart failure (CHF)

Treatment of NYHA functional class II-IV CHF with systolic dysfunction in patients with sinus rhythm and heart rate of at least 70 beats / min in combination with standard therapy, including beta-blocker therapy, or with intolerance or contraindications to the use of beta-blockers.

Use during pregnancy and lactation

Pregnancy

Animal studies have demonstrated the presence of reproductive toxicity, embryotoxicity, and teratogenic effects.

The drug Bravadin is contraindicated for use during pregnancy due to insufficient safety data.

Breast-feeding period

The use of Bravadin during breastfeeding is contraindicated.

It is not known whether ivabradine penetrates into breast milk.

If it is necessary to use Bravadin during lactation, breastfeeding should be discontinued.

Contraindications

·  Hypersensitivity to ivabradine or any of the auxiliary components of the drug.

* Resting heart rate of less than 70 beats / min (before starting 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).

* Sinus node weakness syndrome.

* Sinoatrial blockade.

* Unstable or acute heart failure.

* Dependence on an electrocardiostimulator (conditions in which the heart rate is provided exclusively by an electrocardiostimulator).

* Unstable angina.

* Grade II and III atrioventricular (AV) block.

· Concurrent use with potent inhibitors of isoenzyme of cytochrome P4503 And 4, such as antifungal agents of the group of azoles (ketoconazole, Itraconazole), the macrolide antibiotics (clarithromycin, erythromycin for oral use, josamycin, telithromycin), the HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see “Pharmacokinetics” and “Interaction with other medicines”).

* Concomitant use with verapamil or diltiazem, which are moderate inhibitors of the CYP3A4 isoenzyme, which have the ability to reduce heart rate (see the section “Interaction with other drugs”).

* Pregnancy, breast-feeding and use in women of reproductive age who do not follow reliable contraceptive measures (see the section “Use during pregnancy and lactation”).

·  Age up to 18 years (efficacy and safety of the drug in this age group have not been established).

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

Side effects

Ivabradine has been studied in clinical trials involving almost 45,000 patients. The most frequent side effects of ivabradine, changes in light perception (phosphenes) and bradycardia, were dose-dependent and were associated with the mechanism of action of the drug.

List of adverse reactions

The frequency of adverse reactions reported in clinical trials is given in the following gradation: very common (3 1/10); common (3 1/100, < 1/10); uncommon (3 1/1000, < 1/100); rare (3 1/10000, < 1/1000); very rare (

Nervous system disorders:

common: headache, especially in the first month of therapy, dizziness, possibly related to bradycardia;

infrequent: fainting, possibly related to bradycardia.

Visual disturbances:

very common: a change in light perception (phosphenes) was observed in 14.5% of patients and was described as a transient change in brightness in a limited area of the visual field. As a rule, such phenomena were provoked by a sharp change in the intensity of lighting. Phosphenes can also occur, which can have the appearance of a halo, break up the visual image into separate parts (stroboscopic and kaleidoscopic effects), manifest themselves in the form of bright color flashes or multiple images (retinal persistence). Photopsia mostly appeared in the first two months of treatment, but it could occur again later. The severity of photopsia was usually mild or moderate. The appearance of photopsia stopped during the continuation of therapy (in 77.5% of cases) or after its completion. In less than 1% of patients, the appearance of photopsia was the reason for changing their lifestyle or refusing treatment;

often: blurred vision;

infrequently: diplopia, visual impairment.

Hearing disorders and labyrinth disorders:

infrequently: vertigo.

Cardiac disorders:

common: bradycardia in 3.3% of patients, especially in the first 2-3 months of therapy, in > 0.5% of patients developed bradycardia with heart rate 40 beats/min, AV blockade of I degree (prolonged PQ interval on the ECG), ventricular arrhythmia, uncontrolled changes blood pressure, atrial fibrillation was observed in 5.3% of patients treated with ivabradine compared with 3.8% of patients treated with placebo. According to the analysis of combined data from clinical trials with a follow-up period of at least 3 months, the occurrence of atrial fibrillation was observed in 4.86% of patients taking ivabradine, compared with 4.08% in the control groups;

infrequently: palpitation sensation, supraventricular estrasystole;

very rarely: AV block II and III degrees, sinus node weakness syndrome.

Vascular disorders:

often: marked decrease in blood pressure, possibly associated with bradycardia.

Respiratory, thoracic and mediastinal disorders:

infrequently: shortness of breath.

Disorders of the gastrointestinal tract:

infrequently: nausea, constipation, diarrhea, abdominal pain.

Skin and subcutaneous tissue disorders:

infrequently: skin rash, angioedema;

rarely: erythema, pruritus, urticaria.

Musculoskeletal and connective tissue disorders:

infrequently: muscle spasms.

General disorders and disorders at the injection site:

infrequently: asthenia, increased fatigue, possibly associated with bradycardia;

rarely: malaise, possibly associated with bradycardia.

Laboratory and instrumental data:

infrequently: hyperuricemia, eosinophilia, increased plasma creatinine concentration, prolongation of the QT interval on the ECG.

Interaction

Pharmacodynamic interaction

Concurrent use is not recommended

BOS, lengthening the interval QT:

· antiarrhythmic agents, lengthening of the QT interval (eg, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone);

· BOS, lengthening the QT interval is not related to antiarrhythmic drugs (eg, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin intravenous).

Simultaneous use of ivabradine and drugs that prolong the QT interval is not recommended, since a decrease in heart rate may cause an additional prolongation of the QT interval. If simultaneous use is necessary, careful ECG monitoring is required.

Concomitant use that requires caution

Potassium-sparing diuretics (thiazide and loop diuretics)

Hypokalemia may increase the risk of arrhythmia. Since the use of 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, both congenital and caused by the use of drugs.

Pharmacokinetic interaction

CYP3A4 isoenzyme

Ivabradine is metabolized in the liver with the participation of only the CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. It does not affect the metabolism and plasma concentrations of other substrates (potent, moderate and weak inhibitors) of the CYP3A4 isoenzyme. Inhibitors and inducers of the CYP3A4 isoenzyme can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. Inhibitors of the CYP3A4 isoenzyme increase, and inducers of the CYP3A4 isoenzyme reduce the concentration of ivabradine in blood plasma. An increase in the concentration of ivabradine in the blood plasma may cause the risk of developing severe bradycardia (see the section “Special instructions”).

Simultaneous use is contraindicated

Concomitant use with potent inhibitors of the CYP3A4 isoenzyme, such as azole antifungal agents (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated (see section “Contraindications”). Powerful inhibitors of the CYP3A4 isoenzyme-ketoconazole (200 mg once a day) or josamycin (1 g twice a day)increase the average concentration of ivabradine in blood plasma by 7-8 times.

Moderate inhibitors of the CYP3A4 isoenzyme

The concomitant use of ivabradine and diltiazem or verapamil (drugs that reduce heart rate) in healthy volunteers and patients was accompanied by an increase in AUC by 2-3 times and an additional reduction in heart rate by 5 beats / min. This application is contraindicated (see the section “Contraindications”).

Simultaneous use is not recommended

Grapefruit juice

When used concomitantly with grapefruit juice, there was a 2-fold increase in the concentration of ivabradine in blood plasma. During the use of ivabradine, the use of grapefruit juice is not recommended.

Concomitant use that requires caution

Moderate inhibitors of the CYP3A4 isoenzyme

Concomitant use of ivabradine with other moderate inhibitors of the CYP3A4 isoenzyme (for example, fluconazole) is possible if the resting heart rate is more than 70 beats / min. The recommended initial dose of ivabradine is 2.5 mg 2 times a day.

Heart rate monitoring is required.

Inducers of the CYP3A4 isoenzyme

Inducers of the CYP3A4 isoenzyme (for example, rifampicin, barbiturates, phenytoin drugs containing St. John’s wort) may reduce the plasma concentration of ivabradine and its activity and require a higher dose of ivabradine. Simultaneous use of ivabradine at a dose of 10 mg 2 times a day and drugs containing St. John’s wort reduces the AUC of ivabradine by 2 times. Concomitant use of drugs containing St. John’s Wort and ivabradine is not recommended.

Simultaneous use with other drugs

There is no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine when used concomitantly with proton pump inhibitors (omeprazole, lansoprazole), phosphodiesterase-5 inhibitors (sildenafil), HMG-CoA reductase inhibitors (simvastatin), slow calcium channel blockers (BMCC) (amlodipine, lacidipine), digoxin, etc. warfarin.

Ivabradine has no clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin and the pharmacodynamics of acetylsalicylic acid.

Concomitant use of ivabradine with ACE inhibitors, ARA II inhibitors, beta-blockers, diuretics, aldosterone antagonists, short-and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, hypoglycemic agents for oral use, acetylsalicylic acid, and other antiplatelet agents was not accompanied by a change in the safety profile of the therapy.

How to take, course of use and dosage

Inside,2 times a day, in the morning and in the evening during meals (see the section “Pharmacokinetics”).

Symptomatic treatment of stable angina

Before starting therapy or when deciding on dose titration, heart rate should be determined using one of the following methods: serial heart rate measurement, ECG, or 24-hour outpatient follow-up.

The initial dose of Bravadinne should not exceed 5 mg twice daily in patients under 75 years of age.

If symptoms persist for 3-4 weeks, and if the initial dosage is well tolerated, and the resting heart rate remains more than 60 beats / min, the dose can be increased to the next level in patients who received Bravadin at a dose of 2.5 mg (1/2 tablet 5 mg) 2 times a day or 5 mg 2 times a day. The maintenance dose of Bravadin should not exceed 7.5 mg 2 times a day.

The use of Bravadin should be discontinued if the symptoms of angina do not decrease, if there is little improvement, or if there is no clinically significant decrease in heart rate during 3 months of therapy.

If during therapy with Bravadin, the resting heart rate is reduced to less than 50 beats / min or the patient experiences symptoms associated with bradycardia (such as dizziness, fatigue, or a pronounced decrease in blood pressure), it is necessary to reduce the dose of Bravadin to 2.5 mg (1/2 tablet 5 mg) 2 times a day. After reducing the dose, it is necessary to monitor the heart rate (see the section “Special instructions”). If the dose of Bravadin is reduced to less than 50 beats/min or if symptoms of bradycardia persist, then the drug should be discontinued.

CHF

Therapy can be initiated only in patients with a stable course of CHF.

The recommended initial dose of Bravadin is 10 mg per day (1 tablet of 5 mg 2 times a day).

After two weeks of use, the daily dose of Bravadin can be increased to 15 mg (1 tablet 7.5 mg 2 times a day), if the resting heart rate is stable more than 60 beats / min. If the heart rate is consistently below 50 beats/min or if symptoms of bradycardia such as dizziness, fatigue or hypotension occur, the dose can be reduced to 2.5 mg (1/2 tablet of 5 mg) 2 times a day.

If the heart rate is in the range of 50 to 60 beats / min, the recommended maintenance dose of Bravadin is 5 mg 2 times a day.

If the patient’s resting heart rate is consistently less than 50 beats / min during the course of using Bravadin, or if the patient has symptoms of bradycardia, the dose should be reduced to a lower level for patients receiving Bravadin at a dose of 5 mg 2 times a day or 7.5 mg 2 times a day.

If patients receiving Bravadin 2.5 mg (1/2 tablet 5 mg) 2 times a day or 5 mg 2 times a day have a stable resting heart rate of more than 60 beats / min, the dose of Bravadin may be increased.

If the heart rate remains less than 50 beats / min, or the patient continues to have symptoms of bradycardia, the use of Bravadin should be discontinued (see the section “Special instructions”).

Use in patients over 75 years of age

For patients aged 75 years and older, the recommended initial dose of Bravadin 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 Bravadin.

Impaired renal function

For patients with creatinine clearance greater than 15 ml/min, the recommended initial dose of Bravadin is 10 mg per day (1 tablet of 5 mg 2 times a day) (see section “Pharmacokinetics”). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of Bravadin can be increased to 15 mg (1 tablet of 7.5 mg 2 times a day).

Due to the lack of clinical data on the use of Bravadin in patients with creatinine clearance less than 15 ml / min, the drug should be used with caution.

Impaired liver function

In patients with mild hepatic insufficiency (less than 7 points on the Child-Pugh scale), the usual dosage regimen is recommended.

Caution should be exercised when using Bravadin in patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale).

Bravadin is contraindicated in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale), since the use of Bravadin in such patients has not been studied (a significant increase in the concentration of the drug in blood plasma can be expected) (see the sections “Contraindications” and “Pharmacokinetics”).

Overdose

Symptoms

Overdose of Bravadin can lead to severe and prolonged bradycardia.

Treatment

Treatment of severe bradycardia is symptomatic and should be carried out in specialized hospital departments.In the case of a combination of bradycardia with impaired hemodynamic parameters, beta-adrenomimetics (isoprenaline) should be used. If necessary, implantation of an electrocardiostimulator.

Description

5 mg tablets: Oval, biconvex tablets, film-coated in pale orange color, with a risk on one side. View at the break: white rough mass with a film shell of pale orange color.

Tablets 7.5 mg: Round, slightly biconvex tablets, covered with a film-coated pale orange color, with a chamfer. View at the break: white rough mass with a film shell of pale orange color.

Special instructions

Moderate hepatic insufficiency (7-9 points on the Child-Pugh scale), severe renal insufficiency (creatinine clearance less than 15 ml/min), congenital prolongation of the QT interval (see the section “Interaction with other drugs”), simultaneous use of drugs that prolong the QT interval, simultaneous use of grapefruit juice, recent stroke, retinitis pigmentosa, arterial hypotension, CHF NYHA functional Class IV, concomitant use with potassium-sparing diuretics (see section “Interaction with other medicinal products”).

It is contraindicated in persons under the age of 18 (the effectiveness and safety of the drug in this age group have not been established).

Use in patients over 75 years of age

For patients aged 75 years and older, the recommended initial dose of Bravadin 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 Bravadin.

Impaired renal function

For patients with creatinine clearance greater than 15 ml/min, the recommended initial dose of Bravadin is 10 mg per day (1 tablet of 5 mg 2 times a day) (see section “Pharmacokinetics”). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of Bravadin can be increased to 15 mg (1 tablet of 7.5 mg 2 times a day).

Due to the lack of clinical data on the use of Bravadin in patients with creatinine clearance less than 15 ml / min, the drug should be used with caution.

Impaired liver function

In patients with mild hepatic insufficiency (less than 7 points on the Child-Pugh scale), the usual dosage regimen is recommended.

Caution should be exercised when using Bravadin in patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale).

Bravadin is contraindicated in patients with severe hepatic insufficiency (more than 9 points on the Child-Pugh scale), since the use of Bravadin in such patients has not been studied (a significant increase in the concentration of the drug in blood plasma can be expected) (see the sections “Contraindications” and “Pharmacokinetics”).

Insufficient positive effect on clinical outcomes in patients with symptomatic stable angina pectoris

Ivabradine is indicated only as a symptomatic treatment for stable angina pectoris, since ivabradine does not have a positive effect on the incidence of cardiovascular complications (for example, myocardial infarction or death from cardiovascular diseases) in patients with angina pectoris.

Heart rate monitoring

Given the significant variability of heart rate over the course of the day, before starting ivabradine therapy or before increasing the dose of ivabradine in a patient receiving the drug, the resting heart rate should be evaluated in one of the following ways: serial measurement of heart rate at rest, ECG at rest, or 24-hour outpatient ECG monitoring. This assessment should also be performed in patients with low heart rate (especially if the heart rate becomes less than 50 beats / min) or after reducing the dose of ivabradine.

Cardiac arrhythmias

Ivabradine is ineffective for the treatment or prevention of cardiac arrhythmias. The effectiveness of ivabradine decreases with the development of tachyarrhythmias (for example, ventricular or supraventricular tachycardia). Ivabradine is not recommended for use in patients with atrial fibrillation (atrial fibrillation). or other arrhythmias that affect the function of the sinus node.

Patients taking ivabradine have an increased risk of developing atrial fibrillation. Atrial fibrillation was more common among patients who were taking amiodarone or Class I antiarrhythmic drugs simultaneously with ivabradine.

During ivabradine therapy, patients should be clinically monitored for atrial fibrillation (paroxysmal or persistent). In case of clinical indications (for example, worsening of angina pectoris, palpitations, irregular heart rate), ECG monitoring should be included in the current monitoring. Patients should be informed about the signs and subjective symptoms of atrial fibrillation and the need to consult a doctor if such symptoms occur.

If a patient develops atrial fibrillation during ivabradine therapy, the ratio of the expected benefit to the possible risk of continued use of ivabradine should be carefully reviewed.

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

Use in patients with bradycardia

The use of the drug Bravadine is contraindicated in patients with a resting heart rate of less than 70 beats / min before starting therapy.

If the patient’s resting heart rate is reduced to less than 50 beats/min when using Bravadin, or if the patient has symptoms associated with bradycardia (dizziness, fatigue, or a marked decrease in blood pressure), the dose of the drug should be reduced.

If the dose of Bravadin is reduced to less than 50 beats/min or if symptoms associated with bradycardia persist, Bravadin therapy should be discontinued.

Combined use in antianginal therapy

Concomitant use of the drug Bravadin with BMCC, reducing the pulse (verapamil, diltiazem), is not recommended. When used concomitantly with nitrates or BMCC, dihydropyridine derivatives (amlodipine), no changes in the safety profile of the therapy were observed. Concomitant use of dihydropyridine derivatives with BMCC has not been shown to increase the efficacy of ivabradine.

CHF

The possibility of using Bravadin is considered only in patients with a stable course of CHF. When using Bravadin in patients with CHF of NYHA functional class IV, caution should be exercised due to the limited amount of data on its use in this group of patients.

Stroke

The use of Bravadin immediately after a stroke is not recommended due to the lack of data on efficacy and safety during this period.

Visual functions

The drug Bravadin affects the function of the retina of the eye. There is no evidence of a toxic effect of long-term use of bravadin on the retina of the eye (see the section “Pharmacodynamics”). If any visual disturbances occur that are not described in these instructions, the use of Bravadin should be discontinued. Caution should be exercised when using Bravadin in patients with retinal pigmentation degeneration.

Arterial hypotension

Bravadin should be used with caution in patients with arterial hypotension (insufficient clinical data).

The use of Bravadin is contraindicated in patients with severe hypotension (systolic blood pressure less than 90 mm Hg and diastolic blood pressure less than 50 mm Hg).

Atrial fibrillation (atrial fibrillation) – heart rhythm disorders

There is no evidence of an increased risk of developing severe bradycardia when using Bravadin to restore sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to postpone elective electrical cardioversion, the use of Bravadin should be discontinued 24 hours before it is performed.

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

The drug Bravadin is not used in patients with congenital long QT syndrome, as well as in patients taking drugs that prolong the QT interval. If simultaneous use is necessary, strict ECG monitoring is required.

A decrease in heart rate due to the use of the drug Bravadin can aggravate the prolongation of the QT interval and provoke the development of a severe form of arrhythmia, in particular, polymorphic ventricular tachycardia of the “pirouette” type.

Patients with arterial hypertension who need a change in antihypertensive therapy

In a clinical study, increased blood pressure was more common in the ivabradine group (7.1%) than in the placebo group (6.1%).

Such cases were especially frequent immediately after changes in antihypertensive therapy, were temporary in nature and did not affect the effectiveness of ivabradine therapy. When changing antihypertensive therapy in patients with CHF taking Bravadin, blood pressure should be monitored at certain intervals.

Moderate hepatic insufficiency

Caution should be exercised when using Bravadin in patients with moderate hepatic insufficiency (7-9 points on the Child-Pugh scale).

Severe renal failure

Caution should be exercised when using Bravadin in patients with severe renal insufficiency (creatinine clearance less than 15 ml/min).

Special information on excipients

The drug Bravadin contains lactose, so the drug is contraindicated in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

A study was conducted to evaluate the possible effect of ivabradine on the ability to drive a car in healthy volunteers, according to the results of which the ability to drive a car did not change. However, in the post-marketing period, cases of impaired ability to drive vehicles due to symptoms associated with visual impairment were reported.

The drug Bravadin can cause a temporary change in light perception (mainly in the form of photopsy), which should be taken into account when driving vehicles or other mechanisms with a sharp change in light intensity, especially at night.

Form of production

Film-coated tablets,5 mg,7.5 mg.

14 or 15 tablets in a contour cell package made of a combined PVC/PE/PVDC material and aluminum foil.

1,2,4,6,7 contour cell packages (14 tablets each) or 2,4,6 contour cell packages (15 tablets each) together with the instructions for use are placed in a cardboard pack.

Storage conditions

At a temperature not exceeding 25 °C, in the original packaging.

Keep out of reach of children.

Shelf

life is 3 years.

Do not use the drug after the expiration date.

Active ingredient

Ivabradin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Angina, Arrhythmia, Heart Failure