Bravadin tablet film 5 mg pack cont cell/pack card x56

Bravadin is a drug (tablets) that belongs to the pharmacological group of drugs for the treatment of heart diseases. Important features of the drug from the instructions for use:

How to dissolve vascular plaques, normalize blood circulation, blood pressure and forget the way to the pharmacy

• Sold only with a doctor's prescription
• During pregnancy: contraindicated
• When breastfeeding: contraindicated
• In childhood: contraindicated
• For liver dysfunction: contraindicated
• If renal function is impaired: with caution

Compound

Release form and composition

Bravadin is available in the form of film-coated tablets:

• 5 mg tablets: biconvex, oval, pale orange, scored on one side; on the break of the tablet you can see the core in the form of a rough white mass and a pale orange film shell (14 pcs each in blister packs, 1, 2, 4, 6 or 7 packs in a cardboard pack; 15 pcs in blister packs, in a cardboard box 2, 4 or 6 packages);
• 7.5 mg tablets: slightly biconvex, round, pale orange, beveled; on the break of the tablet you can see the core in the form of a rough white mass and a pale orange film shell (14 pcs each in blister packs, 1, 2, 4, 6 or 7 packs in a cardboard pack; 15 pcs in blister packs, in a cardboard box 2, 4 or 6 packs).

Composition per 1 tablet:

• active ingredient: ivabradine (in the form of ivabradine hydrobromide) – 5 mg or 7.5 mg;
• auxiliary components: povidone, colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, croscarmellose sodium;
• film shell: Opadry orange 03N32599 (titanium dioxide, propylene glycol, red iron oxide dye, hypromellose, talc, yellow iron oxide dye).

Pharmacodynamics

Ivabradine is a drug that slows the heart rate, the mechanism of action of which is the selective and specific inhibition of If channels of the sinus node, which controls the spontaneous diastolic depolarization of the sinus node and regulates 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 retinal Ih channels, similar to cardiac If channels, which are involved in causing temporary changes in the visual perception system by changing the retinal response to bright light stimuli. Under provoking conditions (a sharp change in lighting brightness), partial inhibition of Ih channels occurs by ivabradine, which causes a transient change in brightness in a limited area of ​​the visual field (photopsia).

The main pharmacodynamic property of ivabradine is a dose-dependent decrease in heart rate. Analysis of the dependence of the magnitude 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, when there is no increase in the therapeutic effect with a further increase in the dose, which reduces the risk of developing severe bradycardia (heart rate <40 beats /min).

At recommended doses, the decrease in heart rate is about 10–15 beats/min at rest and during physical activity. This leads to a decrease in the load on the myocardium due to a decrease in the myocardial oxygen demand. Ivabradine does not affect intracardiac conduction, myocardial contractility (no negative inotropic effect) or ventricular repolarization:

— in electrophysiological studies, ivabradine did not affect the time of impulse conduction along the atrioventricular or intraventricular pathways, as well as the corrected QT interval;

- in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) from 30 to 45%), ivabradine did not have a negative effect on LVEF.

Pharmacokinetics

Ivabradine is an S-enantiomer that has not demonstrated biological conversion in in vivo studies. The N-desmethylated derivative of ivabradine is the main active metabolite.

Absorption and bioavailability. Ivabradine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration on an empty stomach, reaching Cmax in the blood plasma after approximately 1 hour. Absolute bioavailability is about 40% and is due to the effect of first pass through the liver.

Eating increases the absorption time of ivabradine by approximately 1 hour and increases plasma concentrations from 20 to 30%. It is recommended to take the tablets with food to reduce concentration variability.

Distribution. Ivabradine binds to plasma proteins by approximately 70%, Vss in patients is about 100 l. Cmax of ivabradine in blood plasma after long-term oral administration of a dose of 5 mg 2 times a day is 22 ng/ml (coefficient of variation (CV) = 29%). The average Css in blood plasma is 10 ng/ml (CV = 38%).

Metabolism. Ivabradine is extensively metabolized in the liver and intestines by oxidation via cytochrome P4503A4 (CYP3A4 isoenzyme). The main active metabolite is the N-desmethylated derivative (S18982) with a concentration of about 40% relative to the concentration of the parent substance. Metabolism of this active metabolite also occurs with the participation of the CYP3A4 isoenzyme. Ivabradine has a low affinity for the CYP3A4 isoenzyme and does not demonstrate clinically significant induction or inhibition of the CYP3A4 isoenzyme, therefore, changes in the metabolism or concentration of CYP3A4 isoenzyme substrates in the blood plasma under the influence of ivabradine are unlikely. Conversely, strong inhibitors and inducers of cytochrome P450 can significantly affect the concentration of ivabradine in the blood plasma.

Excretion. T1/2 of ivabradine averages 2 hours (70–75% relative to AUC in blood plasma), effective T1/2 is 11 hours. Total clearance is about 400 ml/min, renal clearance is about 70 ml/min. Excretion of metabolites occurs to the same extent through the intestines and kidneys. About 4% of the dose taken orally is excreted unchanged by the kidneys.

Linearity/nonlinearity. The pharmacokinetics of ivabradine are linear over 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 patients 65 years and older, 75 years and older, and the general patient population.

Renal dysfunction. Changes in the kinetics of ivabradine in patients with renal failure (Cl creatinine 15–60 ml/min) are minimal, because only about 20% of ivabradine and its active metabolite S18982 are excreted by the kidneys.

Liver dysfunction. In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale), the AUC of ivabradine and its metabolite is 20% greater than in patients with normal liver function. Data on the use of ivabradine in patients with moderate hepatic impairment (7–9 points on the Child-Pugh scale) are limited and do not allow us to draw a conclusion about the pharmacokinetics of ivabradine in this group of patients, and in patients with severe hepatic impairment (more than 9 points on the Child-Pugh scale) -Pugh) are missing.

The 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 S18982 when taken in doses of 15–20 mg 2 times a day. At higher doses of the drug, the decrease in heart rate is not proportional to the concentration of ivabradine in the blood plasma and is characterized by a tendency to achieve a plateau effect. High plasma concentrations of ivabradine, which can be achieved with simultaneous use of ivabradine with strong 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.

Bravadin tablet film 5 mg pack cont cell/pack card x56

Bravadin® (Bravadin®) INSTRUCTIONS for the use of the medicinal product for medical use

Registration number: LP 002544 - 250714 Trade name: Bravadin® International nonproprietary name: ivabradine Dosage form: film-coated tablets Composition per 1 tablet 5 mg: Core Active ingredient: Ivabradine hydrobromide 5.864 mg, which corresponds to ivabradine 5 mg Excipients: lactose monohydrate 64.636 mg, microcrystalline cellulose 20.000 mg, povidone 6.000 mg, croscarmellose sodium 2.000 mg, colloidal silicon dioxide 0.500 mg, magnesium stearate 1.000 mg Film coating: Opadry orange 03N325991 3.000 mg

for 1 tablet 7.5 mg:

Core Active ingredient: Ivabradine hydrobromide 8.796 mg, which corresponds to ivabradine 7.5 mg Excipients: lactose monohydrate 96.954 mg, microcrystalline cellulose 30,000 mg, povidone 9,000 mg, croscarmellose sodium 3,000 mg, colloidal silicon dioxide 0.750 mg, magnesium stearate 1,500 mg Film coating : Opadry orange 03N325991 4,500 mg

1 Composition of Opadry orange 03N32599: hypromellose 71.714%. titanium dioxide (E171) 15.936%, talc 6.972%, propylene glycol 4.980%, yellow iron oxide dye (E 172) 0.332%, red iron oxide dye (E 172) 0.066%.

Description

Tablets 5 mg. Oval, biconvex, film-coated, pale orange tablets with a score line on one side. Fracture appearance: white rough mass with a pale orange film shell. Tablets 7.5 mg. Round, slightly biconvex, film-coated tablets of pale orange color, with a bevel. Fracture appearance: white rough mass with a pale orange film shell.

Pharmacotherapeutic group: antianginal agent CodeATX: C01EB17

Pharmacological properties Pharmacodynamics

Ivabradine is 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 controls the spontaneous diastolic depolarization of the sinus node and regulates the heart rate (HR). 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 to the If channels of the heart, which are involved in causing temporary changes in the visual perception system by changing the reaction of the retina to bright light stimuli. Under provoking conditions (a sharp change in lighting brightness), partial inhibition of Ih channels by ivabradine occurs, which causes a transient change in brightness in a limited area of ​​the visual field (photopsia). The main pharmacodynamic property 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 ivabradine was carried out with a gradual increase in the dose to 20 mg twice a day and revealed a tendency to achieve a “plateau” effect, when there is no increase in the therapeutic effect with a further increase in dose, which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min).

At recommended doses, the decrease in heart rate is about 10-15 beats/min at rest and during physical activity. This leads to a decrease in the load on the myocardium due to a decrease in the myocardial oxygen demand. Ivabradine does not affect intracardiac conduction, myocardial contractility (no negative inotropic effect) or ventricular repolarization:

• in electrophysiological studies, ivabradine had no effect on the conduction time of impulses along the atrioventricular or intraventricular pathways, as well as on the corrected QT interval, • in patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) from 30 to 45%), ivabradine did not had a negative effect on LVEF. Pharmacokinetics

Ivabradine is an S-enantiomer that has not demonstrated biological conversion in in vivo studies. The N-desmethylated derivative of ivabradine is the main active metabolite.

Absorption and bioavailability Ivabradine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration 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 “first pass” effect through the liver. Eating increases the absorption time of ivabradine by approximately 1 hour and increases plasma concentrations from 20 to 30%. It is recommended to take the tablets with food to reduce concentration variability.

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 long-term oral administration of a dose of 5 mg twice a day is 22 ng/ml (coefficient of variation (CV) = 29%). The average equilibrium concentration in blood plasma is 10 ng/ml (CV = 38%).

Metabolism Ivabradine is largely metabolized in the liver and intestines by oxidation via cytochrome P450 3A4 (CYP3A4 isoenzyme). The main active metabolite is the N-desmethylated derivative (S 18982) with a concentration of about 40% relative to the concentration of the parent substance. Metabolism of this active metabolite also occurs with the participation of the CYP3A4 isoenzyme. Ivabradine has a low affinity for the CYP3A4 isoenzyme and does not demonstrate clinically significant induction or inhibition of the CYP3A4 isoenzyme, therefore, changes in the metabolism or concentration of CYP3A4 isoenzyme substrates in the blood plasma under the influence of ivabradine are unlikely. On the contrary, strong inhibitors and inducers of cytochrome P450 can significantly affect the concentration of ivabradine in blood plasma.

Elimination The half-life (T1/2) of ivabradine is, on average, 2 hours (70-75% relative to the area under the concentration/time curve (AUC) in blood plasma), the effective T1/2 is 11 hours. Total clearance is about 400 ml/min, renal clearance is about 70 ml/min. Excretion of metabolites occurs to the same extent through the intestines and kidneys. About 4% of the dose taken orally 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 patients 65 years and older, 75 years and older, and the general patient population.

Impaired renal function Changes in the kinetics of ivabradine in patients with renal failure (creatinine clearance (CC) 15-60 ml/min) are minimal, since only about 20% of ivabradine and its active metabolite S 18982 are excreted by the kidneys.

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

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 in doses of 15-20 mg twice a day. At higher doses of the drug, the decrease in heart rate is not proportional to the concentration of ivabradine in the blood plasma and is characterized by a tendency to achieve a “plateau” effect. High plasma concentrations of ivabradine, which can be achieved with simultaneous use of ivabradine with strong 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 for use Stable angina Treatment of stable angina in adult patients with normal sinus rhythm: • with intolerance or contraindications to the use of beta-blockers, • in combination with beta-blockers with inadequate control of stable angina 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 increased symptoms of chronic heart failure (CHF)) in patients with CHF, with sinus rhythm and a 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 (BP) 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). •Sick sinus syndrome. •Sinoatrial blockade. •Unstable or acute heart failure. •Presence of an artificial pacemaker operating in constant stimulation mode. •Unstable angina. •Atrioventricular block (AV) of the third degree. • Simultaneous use with strong inhibitors of isoenzymes of the cytochrome P450 3A4 system, 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. •Pregnancy and breastfeeding period. • Age up to 18 years (the effectiveness and safety of the drug in this age group has not been studied). •Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome. With caution: 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 the CYP3A4 isoenzyme and grapefruit juice, asymptomatic left ventricular dysfunction, AV block of the second degree, recent stroke, retinitis pigmentosa, arterial hypotension, CHF IV functional class according to the NYHA classification, simultaneous use with blockers of “slow” calcium channels (BMCC) that reduce heart rate (verapamil or diltiazem), simultaneous use with non-potassium-sparing diuretics. Use during pregnancy and breastfeeding Pregnancy Animal studies have demonstrated the presence of reproductive toxicity, embryotoxicity and teratogenicity. Bravadin® is contraindicated for use during pregnancy due to insufficient safety data. Breastfeeding period The use of Bravadin® during breastfeeding is contraindicated. It is unknown whether ivabradine passes into breast milk. If it is necessary to use the drug Bravadin during lactation, breastfeeding should be discontinued.

Method of administration and dosage: Orally, twice a day (morning and evening) during meals. 6 Stable angina The recommended initial dose is 10 mg per day (1 tablet of 5 mg twice a day). After 3-4 weeks of therapy, the dose can be increased to 15 mg per day (1 tablet of 7.5 mg twice a day) depending on the therapeutic effect. If, while using the drug Bravadin®, the heart rate at rest decreases to less than 50 beats/min, or the patient experiences symptoms associated with bradycardia (dizziness, increased fatigue or a marked decrease in blood pressure), the dose of the drug Bravadin® should be reduced to 2.5 mg (according to 1L tablets 5 mg) twice a day. Therapy with Bravadin should be discontinued if, when the dose of Bravadin is reduced, the heart rate remains less than 50 beats/min or symptoms of severe bradycardia persist.

Chronic heart failure The recommended initial dose is 10 mg per day (1 tablet of 5 mg twice a day). After 2 weeks of therapy, the dose can be increased to 15 mg per day (1 tablet 7.5 mg twice a day), if the heart rate at rest is stable more than 60 beats/min, or reduced to 2.5 mg (1 L tablet 5 mg) twice a day if the heart rate is consistently less than 50 beats/min or the patient experiences symptoms associated with bradycardia (dizziness, fatigue, or a marked decrease in blood pressure). If the heart rate is in the range of 50-60 beats/min, it is recommended to use the drug Bravadin at a dose of 5 mg twice a day. If, while using Bravadin, the resting heart rate decreases to less than 50 beats/min or the patient experiences symptoms associated with bradycardia, for patients receiving Bravadin® at a dose of 5 mg twice daily or 7.5 mg twice daily, the dose of the drug should be reduced. If in patients receiving Bravadin® at a dose of 2.5 mg (1/2 tablet of 5 mg) twice a day or 5 mg twice a day, the resting heart rate is stable more than 60 beats/min, the dose of Bravadin may be adjusted increased. If the heart rate remains less than 50 beats/min or the patient continues to experience symptoms associated with bradycardia, therapy with Bravadin® should be discontinued.

Patients over 75 years of age Patients aged 75 years and older should begin treatment with a lower dose. The recommended starting dose is 2.5 mg (1/2 5 mg tablet) twice daily. In the future, the dose may be increased. 7

Impaired renal function Patients with impaired renal function (creatinine clearance more than 15 ml/min) do not require dose adjustment. The recommended starting dose is 10 mg per day (1 tablet of 5 mg twice a day). After 3-4 weeks of therapy, the dose can be increased to 15 mg per day (1 tablet of 7.5 mg twice a day). Due to insufficient clinical data, Bravadin should be used with caution in patients with CC less than 15 ml/min.

Liver dysfunction

No dose adjustment is required in patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale). Caution should be exercised when using Bravadin in patients with moderate liver failure (7-9 points on the Child-Pugh scale). In patients with severe liver failure (more than 9 points on the Child-Pugh scale), the use of the drug Bravadin is contraindicated.

Children and adolescents The safety and effectiveness of ivabradine in children and adolescents under 18 years of age have not been established.

Side effects The use of ivabradine was studied in clinical studies involving almost 14,000 patients. The most common side effects were dose-dependent and related to the mechanism of action of ivabradine. World Health Organization (WHO) classification of the incidence of side effects: very common ≥ 1/10 common ≥ 1/100 to <, 1/10 uncommon ≥ 1/1000 to <, 1/100 rare ≥ 1/10000 to < , 1/1000 very rare from <, 1/10000 frequency unknown - cannot be estimated from available data. Within each group, adverse effects are presented in order of decreasing severity. Visual disturbances: very common: changes in light perception (photopsia)*, common: blurred vision. Hearing and labyrinthine disorders: uncommon: vertigo. Disorders of the heart and blood vessels: often: uncontrolled blood pressure, bradycardia**, AV block of the first degree (extended PQ interval on the electrocardiogram (ECG)), ventricular extrasystole, infrequently: palpitations, supraventricular extrasystole, marked decrease in blood pressure, possibly associated with bradycardia, very rarely: atrial fibrillation, AV block II and III degrees, sick sinus syndrome. Nervous system disorders: common: headache (especially in the first month of therapy), dizziness, possibly associated with bradycardia, frequency unknown: fainting, possibly associated with bradycardia. Respiratory, thoracic and mediastinal disorders: uncommon: shortness of breath. Skin and subcutaneous tissue disorders: uncommon: angioedema, skin rash; rare: pruritus, erythema, urticaria. Gastrointestinal disorders: uncommon: nausea, constipation, diarrhea. Musculoskeletal and connective tissue disorders: uncommon: muscle spasms. General disorders and administration site conditions: uncommon: asthenia, fatigue, possibly associated with bradycardia, rare: malaise, possibly associated with bradycardia. Laboratory and instrumental data: uncommon: hyperuricemia, eosinophilia, increased plasma creatinine concentration, prolongation of the QT interval on the ECG.

* Changes in light perception (photopsia) were observed in 14.5% of patients and were described as a transient change in brightness in a limited area of ​​the visual field. As a rule, such phenomena were provoked by a sharp change in the intensity of illumination in the visual field. Basically, photopsia appeared in the first two months of therapy with subsequent recurrence. The severity of photopsia was usually mild or moderate. Photopsia stopped while therapy was continued (77.5% of cases) or after its completion. In less than 1% of patients, the appearance of photopsia was the reason for refusal of therapy.

** Bradycardia was observed in 3.3% of patients, especially in the first 2-3 months of therapy, 0.5% of patients developed severe bradycardia with a heart rate less than or equal to 40 beats/min.

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, the use of beta-adrenergic agonists (isoprenaline) is necessary. If necessary, install an artificial pacemaker.

Interaction with other drugs Pharmacodynamic interaction

Concomitant use is not recommended

Medicines 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 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 concomitant use is necessary, careful ECG monitoring is required.

Concomitant use requiring caution

Non-potassium-sparing diuretics (thiazide and loop) 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

Cytochrome P450 3A4 (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. Does not affect the metabolism and plasma concentrations of other substrates (strong, moderate and weak inhibitors) of the CYP3A4 isoenzyme. Inhibitors and inducers of the CYP3A4 isoenzyme may 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 the blood plasma. An increase in the concentration of ivabradine in the blood plasma may cause a risk of developing severe bradycardia (see section "Special Instructions").

Concomitant use is contraindicated

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

Concomitant use is not recommended

Moderate inhibitors of the CYP3A4 isoenzyme The simultaneous 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 decrease in heart rate by 5 beats/min.

Concomitant use requiring 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 60 beats/min. The recommended starting dose of ivabradine is 2.5 mg twice daily. Heart rate control is required.

Grapefruit juice When used simultaneously with grapefruit juice, a twofold increase in the concentration of ivabradine in the blood plasma was observed. Drinking grapefruit juice is not recommended while taking ivabradine.

Inducers of the CYP3A4 isoenzyme 11 Inducers of the CYP3A4 isoenzyme (for example, rifampicin, barbiturates, phenytoin and drugs containing St. John's wort) may reduce the plasma concentration and activity of ivabradine and require the selection of a higher dose of ivabradine. The simultaneous use of ivabradine at a dose of 10 mg twice a day and drugs containing St. John's wort reduces the AUC of ivabradine by 2 times. The simultaneous use of drugs containing St. John's wort and ivabradine is not recommended.

Concomitant use with other drugs There is no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine when used simultaneously with proton pump inhibitors (omeprazole, lansoprazole), phosphodiesterase-5 inhibitors (sildenafil), HMG-CoA reductase inhibitors (simvastatin), BMCC (amlodipine, lacidipine) , digoxin and warfarin. 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. Concomitant use of ivabradine and angiotensin-converting enzyme 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 others antiplatelet drugs were not accompanied by a change in the safety profile of the therapy.

Special instructions Cardiac arrhythmia The drug Bravadin® is ineffective in the treatment or prevention of arrhythmia, its effectiveness is reduced when tachyarrhythmia occurs (for example, ventricular or supraventricular tachycardia). The use of Bravadin is not recommended in patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function. When using the drug Bravadin®, it is recommended to conduct clinical monitoring of patients to detect atrial fibrillation (paroxysmal or permanent form), including an ECG study if there are clinical indications (for example, worsening of angina, the appearance of palpitations, irregular heart rhythm). The risk of developing atrial fibrillation may increase in patients with CHF taking the drug Bravadin. Atrial fibrillation was more common among patients taking ivabradine concomitantly with amiodarone or class I antiarrhythmic drugs. Patients with CHF and intraventricular conduction disorders (left or right bundle branch block) and ventricular dyssynchrony should be closely monitored. Second degree AV block The use of Bravadin® is not recommended in patients with second degree AV block.

Use in patients with bradycardia The use of Bravadin is contraindicated in patients with a heart rate less than 60 beats/min at rest before starting therapy. If, when using the drug Bravadin®, the resting heart rate decreases to less than 50 beats/min or the patient experiences symptoms associated with bradycardia (dizziness, fatigue or a marked decrease in blood pressure), the dose of the drug must be reduced. If, when the dose of Bravadin® is reduced, the heart rate remains less than 50 beats/min or symptoms associated with bradycardia persist, therapy with Bravadin should be discontinued.

Combined use as part of antianginal therapy Simultaneous use of the drug Bravadin® with BMCCs that reduce pulse (verapamil, diltiazem) is not recommended. When used simultaneously with nitrates or BMCC, dihydropyridine derivatives (amlodipine), no changes in the safety profile of the therapy were observed. It has not been established that simultaneous use with BMCA, dihydropyridine derivatives, increases the effectiveness of ivabradine.

Chronic heart failure The possibility of using the drug Bravadin® is considered only in patients with stable CHF. When using the drug Bravadin in patients with CHF IV functional class according to the NYHA classification, caution should be exercised due to the limited amount of data on 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 effectiveness and safety during this period. 13

Visual functions The drug Bravadin® affects the function of the retina. At present, no toxic effects on the retina have been identified, but the effect of Bravadin on the retina with long-term use (over 1 year) is currently unknown. If any visual disturbances that are not described in these instructions occur, the use of Bravadin® should be discontinued. When using the drug Bravadin in patients with retinal pigmentary degeneration, caution should be exercised.

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 arterial hypotension (systolic blood pressure less than 90 mmHg and diastolic blood pressure less than 50 mmHg).

Atrial fibrillation (atrial fibrillation) - heart rhythm disturbances. There is no proven increase in the risk of developing severe bradycardia when using the drug Bravadin when restoring sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to delay elective electrical cardioversion, the use of Bravadin should be discontinued 24 hours before it is performed.

Use in patients with congenital long QT interval syndrome or in patients taking drugs that prolong the QT interval. The drug Bravadin® is not used in patients with congenital long QT interval syndrome, as well as in patients taking drugs that prolong the QT interval. If concomitant 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 require a change in antihypertensive therapy In a clinical study, cases of increased blood pressure were more common in the group of patients taking ivabradine (7.1%) compared with the placebo group (6.1%). Such cases occurred especially often immediately after a change in antihypertensive therapy, were temporary in nature and did not affect the effectiveness of 14 ivabradine therapy. When changing antihypertensive therapy in patients with CHF taking Bravadin®, blood pressure should be monitored at certain intervals.

Moderate liver failure Caution should be exercised when using Bravadin® in patients with moderate liver failure (less than 9 points on the Child-Pugh scale).

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

Special information on excipients The drug Bravadin® contains lactose, therefore the drug is contraindicated in patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Impact on the ability to drive vehicles and other technical devices

A study was conducted to evaluate the possible effect of ivabradine on driving ability in healthy volunteers, and the results showed no changes in driving ability. However, in the post-marketing period, cases of deterioration in the ability to drive vehicles due to symptoms associated with visual impairment have been reported. The drug Bravadin can cause a temporary change in light perception (mainly in the form of photopsia), which should be taken into account when driving vehicles or other mechanisms when there is a sharp change in light intensity, especially at night.

Release form Film-coated tablets, 5 mg, 7.5 mg. 14 or 15 tablets in a blister pack made of combined PVC/PE/PVDC material and aluminum foil. 1, 2, 4, 6, 7 blister packs of 14 tablets each or 2, 4, 6 blister packs of 15 tablets, together with 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 the reach of children. Shelf life: 3 years Do not use the drug after the expiration date. Conditions of release Dispensed by prescription. , 143500, Russia, Moscow region, Istra, st. Moskovskaya, d. 50 in cooperation with JSC "KRKA, d.d., Novo Mesto", Šmarješka cesta 6, 8501 Novo Mesto, Slovenia Representative office of JSC "KRKA, d.d., Novo Mesto" in the Russian Federation / Organization accepting claims consumers: 123022, Russian Federation, Moscow, 2nd Zvenigorodskaya st., 13, building 41.

Indications of the drug Bravadin®

Stable angina. Treatment of stable angina in adult 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 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 increased symptoms of chronic heart failure) in patients with chronic heart failure, with sinus rhythm and a heart rate of at least 70 beats/min.

special instructions

Bravadin should not be used to treat or prevent arrhythmia, as it is ineffective in this case. If tachyarrhythmia occurs, the effectiveness of the drug is reduced. The use of Bravadin is also not recommended for atrial fibrillation or other types of arrhythmias associated with sinus node function.

If there is a feeling of palpitations, worsening of angina pectoris and irregular heart rhythm, it is necessary to conduct clinical observation (including an ECG study) of the patient to identify paroxysmal or persistent atrial fibrillation.

In patients with CHF taking Bravadin, the risk of atrial fibrillation increases. Most often, atrial fibrillation occurs in individuals who simultaneously take class I antiarrhythmic drugs and amiodarone along with ivabradine.

In patients with CHF, when changing antihypertensive therapy, it is necessary to regularly (at certain time intervals) monitor blood pressure.

During treatment with Bravadin, the ability to drive vehicles may deteriorate, which is associated with side effects from the organ of vision, namely photopsia. Particular care must be taken when driving a car or other machinery at night.

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 (SBP less than 90 mm Hg and DBP less than 50 mm Hg);

severe liver failure (more than 9 points on the Child-Pugh scale);

sick sinus syndrome;

sinoatrial block;

unstable or acute heart failure;

the presence of an artificial pacemaker operating in constant stimulation mode;

unstable angina;

atrioventricular (AV) block of the third degree;

simultaneous use with strong inhibitors of isoenzymes of the cytochrome P4503A4 system, 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 ;

lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome;

pregnancy;

breastfeeding period;

age under 18 years (the effectiveness and safety of the drug in this age group have not been studied).

With caution: moderate liver failure (less than 9 points on the Child-Pugh scale), severe renal failure (Cl creatinine 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 isoenzyme CYP3A4 and grapefruit juice, asymptomatic left ventricular dysfunction, AV block of the second degree, recent stroke, pigmentary degeneration of the retina (retinitis pigmentosa), arterial hypotension, CHF IV functional class according to the NYHA classification, simultaneous use with CCBs that reduce heart rate (verapamil or diltiazem ), simultaneous use with non-potassium-sparing diuretics.

Bravadin, 5 mg, film-coated tablets, 28 pcs.

Heart rhythm disturbances.

Bravadin® is not effective in the treatment or prevention of arrhythmia, and its effectiveness is reduced when a tachyarrhythmia occurs (for example, ventricular or supraventricular tachycardia). The use of Bravadin® is not recommended in patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function.

When using the drug Bravadin®, it is recommended to conduct clinical monitoring of patients to detect atrial fibrillation (paroxysmal or permanent form), including an ECG study if there are clinical indications (for example, worsening of angina, the appearance of palpitations, irregular heart rhythm).

The risk of developing atrial fibrillation may increase in patients with CHF taking Bravadin®. Atrial fibrillation was more common in patients taking ivabradine concomitantly with amiodarone or class I antiarrhythmic drugs.

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

AV block of the second degree. The use of Bravadin® is not recommended in patients with second degree AV block.

Use in patients with bradycardia.

The use of Bravadin® is contraindicated in patients with a heart rate less than 60 beats/min at rest before starting therapy.

If, when using the drug Bravadin®, the heart rate at rest decreases to less than 50 beats/min or the patient experiences symptoms associated with bradycardia (dizziness, increased fatigue or a marked decrease in blood pressure), the dose of the drug must be reduced.

If, when the dose of Bravadin® is reduced, the heart rate remains less than 50 beats/min or symptoms associated with bradycardia persist, therapy with Bravadin® should be discontinued.

Combined use as part of antianginal therapy.

The simultaneous use of Bravadin® with pulse-lowering CCBs (verapamil, diltiazem) is not recommended. When used simultaneously with nitrates or CCBs, dihydropyridine derivatives (amlodipine), no change in the safety profile of the therapy was observed. It has not been established that simultaneous use with CCBs, dihydropyridine derivatives, increases the effectiveness of ivabradine.

CHF.

The possibility of using the drug Bravadin® is considered only in patients with stable CHF. When using the drug Bravadin® in patients with CHF IV functional class according to the NYHA classification, caution should be exercised due to the limited amount of data on 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 effectiveness and safety during this period.

Visual functions.

The drug Bravadin® affects the function of the retina. At present, no toxic effects on the retina have been identified, but the effect of Bravadin® on the retina with long-term use (over 1 year) is currently unknown.

If any visual disturbances not listed in this description occur, use of Bravadin® should be discontinued. Caution should be exercised when using Bravadin® in patients with retinal pigmentary 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 arterial hypotension (SBP less than 90 mmHg and DBP less than 50 mmHg).

Atrial fibrillation (atrial fibrillation) - heart rhythm disturbances

. There is no proven increase in the risk of developing severe bradycardia with the use of Bravadin® when restoring sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to delay 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 interval syndrome, as well as in patients taking drugs that prolong the QT interval. If concomitant 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 require changes in antihypertensive therapy.

In a clinical study, cases of increased blood pressure were more common in the group of patients taking ivabradine (7.1%) compared to the placebo group (6.1%).

Such cases occurred especially often immediately after a change 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 liver failure.

Caution should be exercised when using Bravadin® in patients with moderate hepatic impairment (less than 9 points on the Child-Pugh scale).

Severe renal failure.

Caution should be exercised when using the drug Bravadin® in patients with severe renal failure (Cl creatinine less than 15 ml/min).

Special information on excipients.

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

Impact on the ability to drive vehicles and other technical devices.

A study was conducted in healthy volunteers to evaluate the possible effect of ivabradine on driving ability, and the results showed no changes in driving ability. However, in the post-marketing period, cases of deterioration in the ability to drive vehicles due to symptoms associated with visual impairment have been reported.

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

Use during pregnancy and breastfeeding

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

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

The use of Bravadin® during breastfeeding is contraindicated.

It is not known whether ivabradine passes into breast milk. If it is necessary to use the drug Bravadin® during lactation, breastfeeding should be stopped

Side effects

Ivabradine was studied in clinical studies involving nearly 14,000 patients. The most common side effects were dose-dependent and related to the mechanism of action of ivabradine.

WHO classification of the incidence of side effects: very often - ≥1/10; often - from ≥1/100 to <1/10; uncommon - from ≥1/1000 to <1/100; rarely - from ≥1/10000 to <1/1000; very rarely - from <1/10000; frequency unknown—cannot be estimated from available data.

Within each group, adverse effects are presented in order of decreasing severity.

On the part of the organ of vision: very often - changes in light perception (photopsia)*; often - blurred vision.

From the organ of hearing and labyrinthine disorders: infrequently - vertigo.

From the heart and blood vessels: often - uncontrolled blood pressure, bradycardia**, AV block of the first degree (extended PQ interval on the ECG, ventricular extrasystole; infrequently - palpitations, supraventricular extrasystole, marked decrease in blood pressure, possibly associated with bradycardia; very rarely - fibrillation atria, AV block II and III degrees, sick sinus syndrome.

From the nervous system: often - headache (especially in the 1st month of therapy), dizziness, possibly associated with bradycardia; frequency unknown - syncope, possibly associated with bradycardia.

From the respiratory system, chest and mediastinal organs: infrequently - shortness of breath.

From the skin and subcutaneous tissues: infrequently - angioedema, skin rash; rarely - skin itching, erythema, urticaria.

From the gastrointestinal tract: infrequently - nausea, constipation, diarrhea.

From the musculoskeletal and connective tissue side: 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: uncommon - hyperuricemia, eosinophilia, increased plasma creatinine concentration, prolongation of the QT interval on the ECG.

* Changes in light perception (photopsia) were observed in 14.5% of patients and were described as a transient change in brightness in a limited area of ​​the visual field. As a rule, such phenomena were provoked by a sharp change in the intensity of illumination in the visual field. Basically, photopsia appeared in the first two months of therapy with subsequent recurrence. The severity of photopsia was usually mild or moderate. Photopsia stopped while therapy was continued (77.5% of cases) or after its completion. In less than 1% of patients, the appearance of photopsia was the reason for refusal of therapy.

** Bradycardia was observed in 3.3% of patients, especially in the first 2–3 months of therapy; 0.5% of patients developed severe bradycardia with a heart rate less than or equal to 40 beats/min.

Interaction

Pharmacodynamic interaction

Concomitant use is not recommended

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, not related to antiarrhythmic drugs (for example, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for intravenous administration).

The 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 concomitant use is necessary, careful ECG monitoring is required.

Concomitant use requiring caution

Non-potassium-sparing diuretics (thiazide and loop). Hypokalemia may increase the risk of developing 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

Cytochrome P450CYP3A4 (CYP3A4 isoenzyme). Ivabradine is metabolized in the liver using only the CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. Does not affect the metabolism and plasma concentrations of other substrates (strong, moderate and weak inhibitors) of the CYP3A4 isoenzyme.

Inhibitors and inducers of the CYP3A4 isoenzyme may 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 the blood plasma.

An increase in the concentration of ivabradine in the blood plasma may cause a risk of developing severe bradycardia (see “Special Instructions”).

Concomitant use is contraindicated

Concomitant use with strong inhibitors of the CYP3A4 isoenzyme, such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated ( see "Contraindications"). Strong inhibitors of the CYP3A4 isoenzyme - ketoconazole (200 mg 1 time per day) or josamycin (1 g 2 times per day) - increase the average concentration of ivabradine in the blood plasma by 7-8 times.

Concomitant use is not recommended

Moderate inhibitors of the CYP3A4 isoenzyme. The simultaneous 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 decrease in heart rate by 5 beats/min.

Concomitant use requiring 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 60 beats/min. The recommended starting dose of ivabradine is 2.5 mg 2 times a day. Heart rate control is required.

Grapefruit juice. When used simultaneously with grapefruit juice, there was a 2-fold increase in the concentration of ivabradine in the blood plasma. Drinking grapefruit juice is not recommended while taking ivabradine.

Inducers of the CYP3A4 isoenzyme. Inducers of the CYP3A4 isoenzyme (for example, rifampicin, barbiturates, phenytoin and drugs containing St. John's wort) may reduce the plasma concentration and activity of ivabradine and require the selection of a higher dose of ivabradine. The 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. The simultaneous 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 simultaneously with proton pump inhibitors (omeprazole, lansoprazole), PDE-5 inhibitors (sildenafil), HMG-CoA reductase inhibitors (simvastatin), CCBs (amlodipine, lacidipine), digoxin and warfarin.

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.

Concomitant use of ivabradine and 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 agents drugs were not accompanied by a change in the safety profile of the therapy.

Directions for use and doses

Orally, 2 times a day (morning and evening) during meals.

Stable angina. The recommended initial dose is 10 mg/day (1 tablet 5 mg 2 times a day). After 3–4 weeks of therapy, the dose can be increased to 15 mg/day (1 tablet 7.5 mg 2 times a day) depending on the therapeutic effect.

If, while using the drug Bravadin®, the heart rate at rest decreases to less than 50 beats/min or the patient experiences symptoms associated with bradycardia (dizziness, increased fatigue or a marked decrease in blood pressure), the dose of the drug Bravadin® should be reduced to 2.5 mg (according to 1/2 tablet 5 mg) 2 times a day.

Therapy with Bravadin® should be discontinued if, when the dose of Bravadin® is reduced, the heart rate remains less than 50 beats/min or symptoms of severe bradycardia persist.

CHF. The recommended initial dose is 10 mg/day (1 tablet 5 mg 2 times a day). After 2 weeks of therapy, the dose can be increased to 15 mg/day (1 tablet 7.5 mg 2 times a day), if the heart rate at rest is stable more than 60 beats/min or reduced to 2.5 mg (1/2 2 tablets 5 mg) 2 times a day, if the heart rate is consistently less than 50 beats/min or the patient experiences symptoms associated with bradycardia (dizziness, increased fatigue or a marked decrease in blood pressure).

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

If, while using the drug Bravadin®, the resting heart rate decreases to less than 50 beats/min or symptoms associated with bradycardia occur in patients receiving the drug Bravadin® at a dose of 5 mg 2 times a day or 7.5 mg 2 times a day, the dose of the drug should be reduced.

If in patients receiving 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 heart rate at rest is stable more than 60 beats/min, the dose of Bravadin ® can be increased.

If the heart rate remains less than 50 beats/min or the patient continues to experience symptoms associated with bradycardia, therapy with Bravadin® should be discontinued.

Patients over 75 years of age. Patients aged 75 years and older should begin treatment with a lower dose. The recommended starting dose is 2.5 mg (1/2 tablet of 5 mg) 2 times a day. In the future, the dose may be increased.

Renal dysfunction. Patients with impaired renal function (creatinine Cl more than 15 ml/min) do not require dose adjustment. The recommended initial dose is 10 mg/day (1 tablet 5 mg 2 times a day). After 3–4 weeks of therapy, the dose can be increased to 15 mg/day (1 tablet 7.5 mg 2 times a day).

Due to insufficient clinical data, Bravadin® should be used with caution in patients with creatinine Cl less than 15 ml/min.

Liver dysfunction. Dose adjustment is not required in patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale). Caution should be exercised when using Bravadin® in patients with moderate liver failure (7–9 points on the Child-Pugh scale).

In patients with severe liver failure (more than 9 points on the Child-Pugh scale), the use of Bravadin® is contraindicated.

Children and teenagers. The safety and effectiveness of ivabradine in children and adolescents under 18 years of age have not been established.

Instructions for use BRAVADIN®

Ivabradine 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 significant fluctuations in heart rate over time, it is recommended to monitor heart rate, ECG or establish 24-hour outpatient monitoring before starting treatment or titrating the dose. These precautions also apply to patients with low heart rate, especially below 50 beats/min, or after a dose reduction.

Heart rhythm disturbances

Ivabradine is not effective in the treatment or prevention of arrhythmias, and its effectiveness is reduced when tachyarrhythmias (eg, ventricular or supraventricular tachycardia) occur. The use of Bravadin® is not recommended in patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function.

When using the drug Bravadin®, it is recommended to conduct clinical monitoring of patients to detect atrial fibrillation (paroxysmal or permanent form), including an ECG study if there are clinical indications (for example, worsening of angina, the appearance of palpitations, irregular heart rhythm).

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

If atrial fibrillation is detected during treatment, the benefit/risk ratio for its continuation should be assessed.

Patients with CHF and intraventricular conduction disorders (left or right bundle branch block) and ventricular dyssynchrony should be under close medical supervision.

AV block II degree

The use of Bravadin® is not recommended in patients with second degree AV block.

Use in patients with bradycardia

The use of Bravadin® is contraindicated in patients with a heart rate less than 70 beats/min at rest before starting therapy.

If, when using the drug Bravadin®, the heart rate at rest decreases to less than 50 beats/min and remains at this level, or the patient experiences symptoms associated with bradycardia (dizziness, increased fatigue or a marked decrease in blood pressure), the dose of the drug must be reduced. If, when the dose of Bravadin® is reduced, the heart rate remains less than 50 beats/min or symptoms associated with bradycardia persist, therapy with Bravadin® should be discontinued.

Combination therapy with calcium channel blockers

The simultaneous use of bravadin and calcium channel blockers that reduce heart rate (verapamil, diltiazem) is not recommended. With simultaneous use of ivabradine with nitrates or calcium channel blockers, dihydropyridine derivatives (amlodipine), no changes in the safety profile of the therapy were observed. It has not been established that simultaneous use with calcium channel blockers, dihydropyridine derivatives, increases the effectiveness of ivabradine.

Chronic heart failure

The possibility of using the drug Bravadin® is considered only in patients with stable CHF. When using the drug Bravadin® in patients with CHF IV functional class according to the NYHA classification, caution should be exercised due to the limited amount of data on 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 effectiveness and safety during this period.

Visual function

Bravadin® affects the function of the retina. Currently, no toxic effects on the retina have been identified, but the effect of Bravadin® on the retina of the eye with long-term use (over 1 year) is currently unknown. If any visual disturbances not described above occur, use of Bravadin® should be discontinued. Caution should be exercised when using Bravadin® in patients with retinal pigmentary 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 arterial hypotension (BP <90/50 mm Hg).

Atrial fibrillation (atrial fibrillation) - heart rhythm disturbances

There is no proven increase in the risk of developing severe bradycardia with the use of Bravadin® when restoring sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to delay 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

Bravadin® is not used in patients with congenital long QT syndrome, as well as in patients taking medications that prolong the QT interval. If concomitant use is necessary, strict ECG monitoring is required. A decrease in heart rate due to the use of the drug Bravadin® may 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 hypertension who require changes in antihypertensive therapy

In the SHIFT clinical trial, cases of increased blood pressure were more common in the group of patients taking ivabradine (7.1%) compared to the placebo group (6.1%). Such cases occurred especially often immediately after a change 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.

Special information on excipients

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

Impact on the ability to drive vehicles and operate machinery

A study was conducted in healthy volunteers to evaluate the possible effect of ivabradine on driving ability, and the results showed no changes in driving ability. However, ivabradine can cause a temporary change in light perception (mainly in the form of photopsia), which 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.