Bravadin pills 7.5mg №56

Qualitative and quantitative composition

Each film-coated pill contains 5.864 mg or 8.796 mg of ivabradine hydrobromide, which corresponds to 5 mg or 7.5 mg of ivabradine.

Pharmaceutical form

Tablets 5 mg. Oval, biconvex tablets, film coated pale orange, with a risk on one side.

Tablets 7.5 mg. Round, slightly biconvex tablets, film-coated pale orange color, with a facet.

Clinical data

Therapeutic indications

Stable angina pectoris
Treatment of stable angina in adult patients with normal sinus rhythm:
• in case of intolerance or the presence of 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-blockers.
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 heart rate of at least 70 beats / min.

Dosage and administration

Inside, twice a day (morning and evening) during the meal.
Stable angina pectoris
The recommended initial dose is 10 mg per day (1 pill 5 mg twice a day).
After 3-4 weeks of therapy, the dose may be increased to 15 mg per day (1 pill of 7.5 mg twice a day), depending on the therapeutic effect.
If during the use of the drug Bravadin^® The heart rate at rest decreases to less than 50 beats / min, or the patient has symptoms associated with bradycardia (dizziness, increased fatigue or a pronounced decrease in blood pressure), a dose of the drug Bravadin^® It is necessary to reduce to 2.5 mg (&№189; pill 5 mg) twice a day.
Bravadin Therapy^® should be discontinued if at lower doses of the drug Bravadin^® HR 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 pill 5 mg twice a day).
After 2 weeks of therapy, the dose may be increased to 15 mg per day (1 pill of 7.5 mg twice a day), if the heart rate is at rest more stable than 60 beats / min, or reduced to 2.5 mg (&№189; pills 5 mg) twice a day, if the heart rate is consistently less than 50 beats / min or the patient has symptoms associated with bradycardia (dizziness, increased fatigue or a pronounced decrease in blood pressure).
If the value of 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 during the use of the drug Bravadin^® The heart rate at rest decreases to less than 50 beats / min or the patient has symptoms associated with bradycardia for patients receiving the drug Bravadin^® at a dose of 5 mg twice a day or 7.5 mg twice a day, the dose of the drug should be reduced.
If a patient is receiving Bravadin^® in a dose of 2.5 mg (&№189; pill 5 mg) twice a day or 5 mg twice a day, heart rate at rest steadily over 60 beats / min, dose of the drug Bravadin^® may be increased.
If the heart rate remains below 50 beats / min or the patient has symptoms associated with bradycardia, therapy with Bravadin^® should stop.
Patients over 75 years old
Patients aged 75 years and older should begin treatment with a lower dose.
The recommended starting dose is 2.5 mg (1/2 pill 5 mg) twice a day.
In the future, the dose may be increased.
Renal dysfunction
Patients with impaired renal function (CC more than 15 ml / min) do not require dose adjustment.
The recommended initial dose is 10 mg per day (1 pill 5 mg twice a day). After 3-4 weeks of therapy, the dose may be increased to 15 mg per day (1 pill of 7.5 mg twice a day).
Due to the lack of clinical data, the drug Bravadin^® should be used with caution in patients with QA less than 15 ml / min.
Liver dysfunction
Dose adjustment is not required in patients with mild liver failure (up to 7 on the Child-Pugh scale). Caution must be exercised when using the drug Bravadin.^® in patients with moderate hepatic impairment (7- 9 points on the Child-Pugh scale).
Patients with severe liver failure (more than 9 points on the Child-Pugh scale) use of the drug Bravadin^® contraindicated.
Kids and teens
The safety and effectiveness of ivabradine in children and adolescents under the age of 18 years have not been established.

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.
• The presence of an artificial pacemaker working in the mode of constant stimulation.
• Unstable angina.
• Atrioventricular block (AV) III degree.
• The simultaneous use of potent inhibitors of cytochrome P450 3A4, such as antifungals group azoles (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, Erythromycin for oral, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone.
• Pregnancy and breastfeeding period.
• Age up to 18 years (the efficacy and safety of the drug in this age group has not been studied).
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

With caution: moderately severe liver failure (less than 9 points on the Child-Pugh scale), severe renal failure (QC less than 15 ml / min), congenital lengthening of the QT interval, simultaneous use of drugs (LS), prolonging the QT interval, simultaneous use of moderate inhibitors and inducers of CYP3A4 isoenzyme and grapefruit juice, asymptomatic left ventricular dysfunction, AV block II, recently suffered a stroke, retinal pigment degeneration (arterial hypotension, CHF IV function NYHA classification, simultaneous use with blockers of “slow” Calcium channels (BMCC), which reduce heart rate (verapamil or diltiazem), simultaneous use with non-calcium-sparing diuretics.

Special instructions and precautionary measures

Heart rhythm disorders
Drug bravadin^® ineffective in the treatment or prevention of arrhythmia, its effectiveness decreases when tachyarrhythmias occur (for example, ventricular or supraventricular tachycardia). Use of the drug Bravadin^® not recommended in patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with the function of the sinus node.
When using the drug Bravadin^® It is recommended to conduct clinical monitoring of patients for atrial fibrillation (paroxysmal or permanent form), including an ECG study with clinical indications (for example, worsening of angina, the appearance of a heartbeat, irregular heart rhythm).
The risk of developing atrial fibrillation may increase in patients with CHF who take the drug Bravadin^®. Atrial fibrillation was more common among patients who were simultaneously taking ivabradine with Amiodarone or class I antiarrhythmic drugs.
Patients with CHF and disorders of intraventricular conduction (blockade of the left or right leg of the bundle of His) and ventricular dyssynchrony should be closely monitored.
AV block II degree
Use of the drug Bravadin^® not recommended in patients with AV block
II degree.
Use in patients with bradycardia
Use of the drug Bravadin^® contraindicated in patients with 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 has symptoms associated with bradycardia (dizziness, increased fatigue, or a marked decrease in blood pressure), the dose of the drug should be reduced.
If at lower doses of the drug Bravadin^® HR remains less than 50 beats / min or symptoms associated with bradycardia, Bravadin therapy remain.^® should stop.
Combined use as part of antianginal therapy
Simultaneous use of the drug Bravadin^® with BMCC, which reduces pulse (verapamil, diltiazem) is not recommended. With simultaneous use with nitrates or BMCC, dihydropyridine derivatives (amlodipine), no change in the safety profile of the therapy was observed. It has not been established that simultaneous use with BMCC, dihydropyridine derivatives, increases the effectiveness of ivabradine.
Chronic heart failure
The possibility of using the drug Bravadin^® is considered only in patients with a stable course of CHF. When using the drug Bravadin^® in patients with CHF
Care should be taken in relation to the limited amount of application data for this group of patients.
Stroke
The use of the drug Bravadin is not recommended.^® immediately after a stroke due to the lack of data on efficacy and safety during this period.
Visual function
Drug bravadin^® affects the function of the retina. Currently, no toxic effects on the retina have been identified, but the effect of the drug Bravadin^® on the retina with prolonged use (over 1 year) is currently unknown.
In case of any visual disturbances that are not described in this manual, use of the drug Bravadin^® should stop. When using the drug Bravadin^® Caution should be exercised in patients with retinal pigment degeneration.
Hypotension
Drug bravadin^® should be used with caution in patients with arterial hypotension (insufficient clinical data).
Use of the drug Bravadin^® contraindicated in patients with severe hypotension (systolic blood pressure less than 90 mm Hg and diastolic blood pressure less than
50 mmHg.).
Atrial fibrillation (atrial fibrillation) - cardiac arrhythmias
Not proven to increase the risk of developing severe bradycardia with the use of the drug Bravadin^® when restoring sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if possible, to delay planned electrical cardioversion, use of the drug Bravadin^® should stop 24 hours before its holding.
Use in patients with congenital long QT interval syndrome or in patients taking drugs that prolong the QT interval
Drug bravadin^® not used in patients with congenital long QT interval syndrome, as well as in patients taking drugs that prolong the QT interval. If necessary, simultaneous use requires strict ECG monitoring.
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.
Hypertensive patients requiring 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 particularly often immediately after a change in antihypertensive therapy, were temporary and did not affect the effectiveness of therapy with ivabradine. When changing antihypertensive therapy in patients with CHF taking the drug Bravadin^®should monitor blood pressure at regular intervals.
Mild hepatic impairment
Caution must be exercised when using the drug Bravadin.^® in patients with moderate hepatic impairment (less than 9 points on the Child-Pugh scale).
Severe renal failure
Caution must be exercised when using the drug Bravadin.^® in patients with severe renal failure (CC less than 15 ml / min).
Special information on excipients
Drug bravadin^® contains lactose, so the drug is contraindicated in patients with lactase deficiency, lactose intolerance, and glucose-galactose malabsorption syndrome.

Interaction with other drugs

Patients receiving Warfarin or other anticoagulants and orlistat may experience a decrease in prothrombin level, an increase in the international normalization factor (INR), which leads to changes in hemostatic parameters.
Interaction with Amitriptyline, biguanides, Digoxin, fibrates, Fluoxetine, Losartan, phenytoin, oral contraceptives, phentermine, GITS Nifedipine, delayed-release nifedipine, sibutramine, Furosemide, Captopril, a home nol. Increases the bioavailability and hypolipidemic effect of pravastatin, increasing its plasma concentration by 30%. A decrease in body weight can improve the metabolism of diabetic patients, as a result of which it is necessary to reduce the dose of oral hypoglycemic agents. Treatment with orlistat potentially disrupts the absorption of fat-soluble Vitamins (A, D, E, K). If taking multivitamins is recommended, they should be taken no earlier than 2 hours after taking orlistat or at bedtime.
With the simultaneous use of orlistat and cyclosporine, a decrease in plasma concentration of cyclosporine was noted, therefore it is recommended to determine the concentration of cyclosporine in blood plasma more often.
In patients receiving amiodarone, clinical observation and monitoring of ECG should be carried out more thoroughly, as described are cases of a decrease in the concentration of amiodarone in the blood plasma.

Pregnancy and breastfeeding

Pregnancy
Animal studies have demonstrated the presence of reproductive toxicity, embryotoxicity and teratogenic action.
Drug bravadin^® contraindicated for use in pregnancy due to insufficient safety data.
Breastfeeding period
Use of the drug Bravadin^® during breastfeeding is contraindicated.
It is not known whether ivabradine passes into breast milk.
If necessary, use the drug Bravadin^® during lactation, breastfeeding should be discontinued.

Influence on ability to drive a car and other mechanisms

A study was conducted to assess the possible impact of Ivabradine on the ability to drive a car with the participation of healthy volunteers, as a result of which the ability to drive a car did not change. However, in the post-marketing period, there were reported cases of deterioration in the ability to drive vehicles due to symptoms associated with visual impairment.
Drug bravadin^® may cause a temporary change in light perception (mainly in the form of a photopsia), which should be taken into account when driving vehicles or other mechanisms with a sharp change in the intensity of light, especially at night.

Side effects

Side effects
The use of ivabradine has been studied in clinical studies involving almost
14,000 patients. The most common side effects were dose-dependent in nature and were associated with the mechanism of action of ivabradine.
Classification of the incidence of side effects of the World Health Organization (WHO):
very often ≥ 1/10
often from ≥ 1/100 to <1/10
infrequently from ≥ 1/1000 to <1/100
rarely from ≥ 1/10000 to <1/1000
very rarely from <1/10000
frequency unknown cannot be estimated based on available data.
In each group, undesirable effects are presented in order of decreasing severity.
Violations by the organ of vision:
very often: a change in light perception (photopsy) *;
often: blurred vision.
Disturbances from an organ of hearing and labyrinth disturbances:
infrequently: vertigo.
Violations of the heart and blood vessels:
often: uncontrolled blood pressure, bradycardia **, AV block I degree (prolonged PQ interval on the electrocardiogram (ECG)), ventricular premature beats;
infrequently: palpitations, supraventricular extrasystole, marked reduction in blood pressure, possibly associated with bradycardia;
very rarely: atrial fibrillation, AV block II and III degree, sick sinus syndrome.
Nervous system disorders:
often: headache (especially in the first month of therapy), dizziness, possibly associated with bradycardia;
frequency unknown: syncope, possibly associated with bradycardia.
Disorders of the respiratory system, organs of the chest and mediastinum:
infrequently: shortness of breath.
Violations of the skin and subcutaneous tissues:
infrequently: angioedema, skin rash;
rarely: pruritus, erythema, urticaria.
Violations of the gastrointestinal tract:
infrequently: nausea, constipation, diarrhea.
Disorders of the musculoskeletal and connective tissue:
infrequently: muscle cramps.
General disorders and disorders at the site of administration:
infrequently: asthenia, fatigue, possibly associated with bradycardia;
seldom: malaise, possibly associated with bradycardia.
Laboratory and instrumental data:
infrequently: hyperuricemia, eosinophilia, increased plasma creatinine concentration, prolongation of the QT interval on the ECG.
* A change in light perception (photopsia) was noted in 14.5% of patients and was described as a transient change in brightness in a limited area of ​​the visual field. As a rule, such phenomena were provoked by a sharp change in the intensity of illumination in the zone of the visual field. In general, photopsia appeared in the first two months of therapy, followed by repetition. The severity of photopsia, as a rule, was mild or moderate. Photopsia was stopped with continued therapy (77.5% of cases) or after its completion. In less than 1% of patients, the appearance of photopsia was the reason for refusing 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 the drug Bravadin^® can lead to severe and prolonged bradycardia.
Treatment
Treatment of severe bradycardia is symptomatic and should be carried out in the conditions of specialized departments of the hospital. In the case of a combination of bradycardia with impaired hemodynamic parameters, beta-adrenomimetic drugs (isoprenaline) are necessary. If necessary, install an artificial pacemaker.

Pharmacological properties

Pharmacodynamics

Pharmacotherapeutic group: antianginal agent

Pharmacological properties
Pharmacodynamics
Ivabradine is a drug that slows the rhythm of the heart, the mechanism of action of which lies in the selective and specific inhibition of the If channels of the sinus node, which controls 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 duration of the impulses along the atrial, atrioventricular and intraventricular pathways, as well as myocardial contractility and ventricular repolarization.
Ivabradine can also interact with the Ih retinal channels, similar to If channels of the heart, which are involved in the occurrence of a temporary change in the visual perception system due to a change in the response of the retina to bright light stimuli. In provoking conditions (a sharp change in the brightness of the illumination), partial inhibition of the Ivabradine Ih channel occurs, which causes a transient change in brightness in a limited area of ​​the visual field (photopsia).
The main pharmacodynamic property of ivabradine is dose-dependent decrease in heart rate. Analysis of the dependence of the HR reduction on the dose of ivabradine was carried out with a gradual increase in dose to 20 mg twice a day and revealed a tendency to achieve a “plateau” effect when the therapeutic effect does not increase with a further increase in dose, which reduces the risk of developing severe bradycardia (HR 40 beats / min).
At recommended doses, the decrease in heart rate is about 10-15 beats / min at rest and during exercise.This leads to a decrease in the load on the myocardium due to a decrease in the oxygen demand of the myocardium. Ivabradine does not affect intracardiac conduction, myocardial contractility (no negative inotropic action) or ventricular repolarization:
- In electrophysiological studies, Ivabradine did not affect the time of the impulses 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 adversely affect LVEF.

Pharmacokinetics

Ivabradine is an S-enantiomer that does not demonstrate biological transformation in in vivo studies. 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 ingestion on an empty stomach, reaching the maximum concentration (Cmax) in the blood plasma after approximately 1 hour. Absolute bioavailability is about 40% and is due to the effect of "primary passage" through the liver.
Eating increases the time of absorption of ivabradine by approximately 1 hour and increases plasma concentration from 20 to 30%. It is recommended to take the pills during the meal in order to reduce the concentration variability.
Distribution
Ivabradine binds to plasma proteins at about 70%, the volume of distribution in patients in equilibrium is about 100 liters. Cmax of ivabradine in the blood plasma after prolonged 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 plasma is 10 ng / ml (KV = 38%).
Metabolism
Ivabradine is extensively metabolized in the liver and intestines by oxidation with 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 starting material. The metabolism of this active metabolite also occurs with the participation of the CYP3A4 isoenzyme. Ivabradine has a low degree of affinity for the CYP3A4 isoenzyme, does not demonstrate clinically significant induction or inhibition of the CYP3A4 isoenzyme, so a change in the metabolism or concentration of the plasma isoenzyme CYP3A4 under the action of ivabradine is unlikely.On the contrary, strong inhibitors and inductors of cytochrome P450 can significantly affect the concentration of ivabradine in the blood plasma.
Removal
The half-life (T&№189;) of ivabradine is, on average, 2 hours (70-75% relative to the area under the concentration / time curve (AUC) in blood plasma), the effective T&№189; 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 the kidneys. About 4% of the ingested dose is excreted unchanged by the kidneys.
Linearity / nonlinearity
Ivabradine pharmacokinetics is linear in the dose range of 0.5-24 mg.
Special patient groups
Elderly and senile patients
Pharmacokinetic parameters (AUC and Сmax) do not significantly differ in patients 65 years and older, 75 years and older, and the general population of patients.
Renal dysfunction
Ivabradine kinetics changes in patients with renal insufficiency (creatinine clearance (KK) 15-60 ml / min) is minimal, since only about 20% of ivabradine and its active metabolite S 18982 are excreted by the kidneys.
Liver dysfunction
In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale), AUC of ivabradine and its metabolite is 20% more 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) is limited and does not allow to conclude about the features of the pharmacokinetics of Ivabradine in this group of patients, and in patients with severe liver failure (more than 9 points on the Child -Pu) absent.
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 S 18982 when taken in doses
15–20 mg twice daily. 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 concentrations of Ivabradine in the blood plasma, 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,however, this risk is reduced when used simultaneously with moderate inhibitors of the CYP3A4 isoenzyme.

Pharmaceutical data

List of excipients

Excipients: lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, colloidal silicon dioxide, Magnesium stearate
Shell film: Opredra orange 03H325991.

Storage conditions

List B.
At a temperature not higher than 25 ° С, in the original package.
Keep out of the reach of children.

Release form

Film-coated tablets, 5 mg, 7.5 mg.
On 14 pills in a blister strip packaging from the combined material PVC / PE / PVDH and aluminum foil.
2 or 4 blister packs on (14 tablets) together with instructions for use are placed in a pack of cardboard.

Instructions for drug preparation and handling

No special requirements.