Bravadin, 5 mg 56 pcs.

Heart failure, Arrhythmia, Angina

Symptomatic therapy of stable angina

Symptomatic therapy of stable angina in coronary heart disease (CHD) in adult patients with normal sinus rhythm and heart rate of at least 70 bpm:

– if intolerant or contraindicated to the use of beta-adrenoblockers;

– in combination with beta-adrenoblockers in inadequate control of stable angina against optimal dose of beta-adrenoblocker.

The therapy of chronic heart failure (CHF)

Therapy of CHF of functional class II-IV according to NYHA classification with systolic dysfunction in patients with sinus rhythm and HR of at least 70 bpm in combination with standard therapy, including therapy with beta-adrenoblockers, or with intolerance or contraindications to the use of beta-adrenoblockers.

Active ingredient

Composition

for 1 tablet 5 mg/7.5 mg:

Core:

Active substance:

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

: justify;”> Auxiliary substances:

Lactose monohydrate,microcrystalline cellulose, povidone-K30,croscarmellose sodium, colloidal silicon dioxide, magnesium stearate

: justify;”> Shell film:

Opadray orange 03H325991

1Composition of Opadray Orange 03H32599:

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

How to take, the dosage

Orally, twice daily, morning and evening with meals (see section “Pharmacokinetics”).

Symptomatic therapy for stable angina

Before therapy or when deciding on dose titration, heart rate should be determined by one of the following methods: serial heart rate measurement, ECG, or 24-hour ambulatory observation.

The starting dose of Bravadinone should exceed 5 mg twice daily in patients under 75 years of age.

If symptoms persist for 3-4 weeks, and if the initial dose is well tolerated and the resting HR remains greater than 60 bpm, the dose may be increased to the next level in patients receiving Bravadine at 2.5 mg (1/2 tablet 5 mg) 2 times daily or 5 mg 2 times daily. The maintenance dose of Bravadine should not exceed 7.5 mg 2 times daily.

The use of Bravadine should be discontinued if the symptoms of angina do not decrease, if there is little improvement, or if there is no clinically significant reduction in HR over 3 months of therapy.

If during Bravadine therapy the resting HR falls below 50 bpm or if the patient develops bradycardia-related symptoms (such as dizziness, increased fatigue, or markedly decreased BP), the Bravadine dose should be reduced to 2.5 mg (1/2 tablet of 5 mg) 2 times daily. After reducing the dose, HR should be monitored (see section “Special Precautions”).If during the reduction of the dose of the drug Bravadin HR remains less than 50 bpm or the symptoms of bradycardia are preserved, the drug should be discontinued.

CSN

Therapy may be started only in patients with a stable course of CSN.

The recommended initial dose of Bravadine is 10 mg per day (1 tablet of 5 mg twice daily).

After two weeks of use, the daily dose of Bravadine may be increased to 15 mg (1 tablet of 7.5 mg 2 times daily) if resting HR is consistently greater than 60 bpm. If HR is steadily lower than 50 bpm or if bradycardia symptoms, such as dizziness, increased fatigue or arterial hypotension are present, the dose may be decreased to 2.5 mg (1/2 tablet 5 mg) 2 times per day.

If the HR is between 50 and 60 bpm, the recommended maintenance dose of Bravadine is 5 mg 2 times daily.

If the resting HR is consistently less than 50 bpm during use of Bravadine, or if the patient has symptoms of bradycardia, the dose should be reduced to a lower level for patients receiving Bravadine at 5 mg 2 times daily or 7.5 mg 2 times daily.

If patients receiving Bravadine at a dose of 2.5 mg (1/2 tablet 5 mg) 2 times daily or 5 mg 2 times daily have a resting HR consistently greater than 60 bpm, the Bravadine dose may be increased.

If HR remains less than 50 bpm, or if the patient still has symptoms of bradycardia, the use of Bravadine should be stopped (see “Special Precautions”).

Application in patients over 75 years

For patients aged 75 years and older, the recommended starting dose of Bravadine is 2.5 mg (1/2 tablet, 5 mg) 2 times daily. Subsequently it is possible to increase the dosage of Bravadin.

Renal dysfunction

For patients with CKD over 15 ml/min, the recommended starting dose of Bravadine is 10 mg per day (1 tablet 5 mg 2 times daily) (see “Pharmacokinetics” section). See section “Pharmacokinetics”). After 3-4 weeks of use, depending on the therapeutic effect, the dose of Bravadin may be increased to 15 mg (1 tablet of 7.5 mg 2 times per day).

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

Hepatic dysfunction

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

Caution should be exercised when using Bravadine in patients with moderate hepatic impairment (7-9 Child-Pugh scores).

Bravadine is contraindicated in patients with severe hepatic impairment (greater than 9 points on the Child-Pugh scale), because the use of Bravadine in such patients has not been studied (a significant increase in plasma concentrations can be expected) (see sections “Contraindications” and “Pharmacokinetics”).

Interaction

Pharmacodynamic interaction

Simultaneous use is not recommended

Preventive drugs that lengthen the interval QT:

– antiarrhythmic drugs that prolong the QT interval (e.g., quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone);

– Drugs that prolong the QT interval that are not antiarrhythmic drugs (e.g., pimozide, ziprasidone, certindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for intravenous administration).

Simultaneous use of ivabradine and QT interval prolonging drugs is not recommended because HR shortening can cause additional QT interval prolongation. If simultaneous use is necessary, a careful ECG monitoring is required.

Simultaneous use requiring caution

Kalinergic diuretics (thiazide and “loop” diuretics)

Hypokalemia may increase the risk of arrhythmias. Because ivabradine use may cause bradycardia, the combination of hypokalemia and bradycardia is a predisposing factor for the development of severe arrhythmia, especially in patients with prolonged QT syndrome, both congenital and drug-induced.

Pharmacokinetic interaction

Isoenzyme CYP3A4

Ivabradine undergoes metabolism in the liver involving only the CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. It has no effect on the metabolism and plasma concentrations of other substrates (potent, moderate and weak inhibitors) of CYP3A4 isoenzyme. CYP3A4 inhibitors and inducers may interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. CYP3A4 isoenzyme inhibitors increase and CYP3A4 isoenzyme inducers decrease the plasma concentration of ivabradine. Increasing the plasma concentration of ivabradine may cause the risk of severe bradycardia (see section “Cautions”).

Simultaneous use is contraindicated

Simultaneous use is not recommended

Grapefruit juice

A 2-fold increase in the plasma concentration of ivabradine was noted when used concomitantly with grapefruit juice. Consumption of grapefruit juice is not recommended during the use of ivabradine.

Simultaneous use requiring caution

Moderate isoenzyme inhibitorsCYP3A4

The concomitant use of ivabradine with other moderate CYP3A4 isoenzyme inhibitors (e.g., fluconazole) is possible if the resting HR is greater than 70 bpm.The recommended starting dose of ivabradine is 2.5 mg 2 times daily.

The heart rate should be controlled.

Isoenzyme inducers CYP3A4

Special Instructions

Moderate hepatic impairment (7-9 Child-Pugh scores), severe renal impairment (CKI less than 15 ml/min), congenital prolongation of the QT interval (see section “Interaction with other drugs.

Prevalence and concomitant use of QT interval prolonging agents (Drugs), concomitant use of grapefruit juice, recent stroke, retinal pigmentary degeneration (retinitispigmentosa), arterial hypotension, CHF class IV according to NYHA classification, concomitant use with potassium-saving diuretics (see section “Interaction with other medicinal products”).

Persons under 18 years of age are contraindicated (efficacy and safety of the drug in this age group have not been established).

Application in patients over 75 years old

For patients aged 75 years and older, the recommended starting dose of Bravadin is 2.5 mg (1/2 tablet of 5 mg) 2 times daily. Subsequently it is possible to increase the dosage of Bravadin.

Renal dysfunction

For patients with CKD over 15 ml/min, the recommended starting dose of Bravadine is 10 mg per day (1 tablet 5 mg 2 times daily) (see “Pharmacokinetics” section). See section “Pharmacokinetics”). After 3-4 weeks of use, depending on the therapeutic effect, the dose of Bravadin may be increased to 15 mg (1 tablet of 7.5 mg 2 times per day).

Due to the lack of clinical data concerning the use of Bravadin in patients with CK rates lower than 15 ml/min, the drug should be used with caution.

Hepatic dysfunction

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

Caution should be exercised when using Bravadine in patients with moderate hepatic impairment (7-9 Child-Pugh scores).

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

Lack of benefit with respect to clinical outcomes in patients with symptomatic stable angina pectoris

Ivabradine is indicated only as symptomatic therapy for stable angina, because ivabradine has no positive effect on the incidence of cardiovascular complications (e.g., myocardial infarction or cardiovascular death) in patients with angina.

Monitoring HR

Given the significant variability in HR during the day, resting HR should be assessed in a patient receiving ivabradine before starting therapy or before increasing the dose of ivabradine by one of the following methods: serial resting HR measurement, resting ECG, or 24-hour ambulatory ECG monitoring. This evaluation should also be performed in patients with low HR (especially if the HR becomes less than 50 bpm) or after reducing the dose of ivabradine.

Heart rhythm disorders

Ivabradine is ineffective in the treatment or prevention of heart rhythm disorders. The efficacy of Ivabradine is reduced with the development of tachyarrhythmias (e.g., ventricular or supraventricular tachycardia). Ivabradine is not recommended for patients with atrial fibrillation (atrial fibrillation) or other arrhythmias affecting sinus node function.

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

During therapy with ivabradine, patients should be clinically monitored for atrial fibrillation (paroxysmal or permanent). If clinically indicated (e.g., worsening angina, palpitations, irregular heart rhythm), ECG monitoring should be included in routine monitoring. Patients should be informed about the signs and subjective symptoms of atrial fibrillation and the need to consult a physician if such symptoms occur.

If patients experience atrial fibrillation during ivabradine therapy, the expected benefit versus possible risk of continued use should be carefully reviewed.

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

Application in patients with bradycardia

The use ofBravadine is contraindicated in patients with resting heart rate less than 70 bpm before therapy.

If resting heart rate is less than 50 bpm when using Bravadine or if bradycardia-related symptoms (dizziness, increased fatigue, or markedly decreased blood pressure) are present, the drug dose should be decreased.

If the HR remains less than 50 bpm or symptoms associated with bradycardia persist when the Bravadine dose is reduced, therapy with Bravadine should be stopped.

Combined use as part of antianginal therapy

Simultaneous use of Bravadine with heart rate-limiting BMCCs (verapamil, diltiazem) is not recommended. When concomitant use with nitrates or dihydropyridine derivatives (amlodipine), no changes in the safety profile of the therapy were noted. It has not been found that concomitant use with BMCCs, dihydropyridine derivatives, increases the efficacy of ivabradine.

CRCF

The use of Bravadin is considered only in patients with stable course of CHF. Caution should be exercised when using Bravadin in patients with CHF of functional class IV according to NYHA classification due to the limited 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.

Sight function

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

Arterial hypotension

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

The use of Bravadine is contraindicated in patients with severe arterial hypotension (systolic BP less than 90 mm Hg and diastolic BP less than 50 mm Hg).

Atrial fibrillation (atrial fibrillation) – heart rhythm disorders

There has been no evidence of an increased risk of severe bradycardia with Bravadine when sinus rhythm is restored during pharmacological cardioversion. Nevertheless, due to the lack of sufficient data, if it is possible to delay the planned electric cardioversion, the use of Bravadine should be stopped 24 hours before it is performed.

Application in patients with congenital prolonged interval syndrome QTor in patients taking medications that prolong the interval QT

The drug Bravadine is not used in patients with congenital prolonged QT interval syndrome or in patients taking QT interval prolonging drugs. If it is necessary to use simultaneously a strict control of ECG is required.

The heart rate slowing due to the use of Bravadine may worsen the QT interval prolongation and provoke a severe form of arrhythmia, particularly polymorphic ventricular tachycardia like pirouette.

Patients with arterial hypertension who require a change in hypotensive therapy

In the clinical trial, cases of BP elevation occurred more frequently in the group of patients taking ivabradine (7.1%) compared with the placebo group (6.1%).

These cases occurred particularly often immediately after changes in hypotensive therapy, were temporary and did not affect the effectiveness of ivabradine therapy. When changing hypotensive therapy in patients with CHF taking Bravadine, BP should be monitored at regular intervals.

Moderate hepatic impairment

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

Severe renal failure

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

Special information on excipients

The drug Bravadine 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 driving ability in healthy volunteers, and the results showed no change in driving ability. However, in the post-marketing period, cases of impairment of driving ability due to symptoms associated with visual impairment have been reported.

The drug Bravadine may cause temporary changes in light perception (mainly in the form of photopsia), which should be taken into account when driving motor vehicles or other mechanisms under sudden changes in light intensity, especially at night.

Synopsis

Tablets 5 mg: Oval, biconvex pale orange film-coated tablets with a rib on one side. View on the break: white rough mass with a film coating of pale orange color.

Tablets 7.5 mg: Round, slightly biconvex pale orange film-coated tablets, with bevel. View on the break: white rough mass with a film coating of pale orange.

Contraindications

– Hypersensitivity to ivabradine or any of the excipients of the drug.

– Resting heart rate less than 70 bpm (before treatment).

– Cardiogenic shock.

– Acute myocardial infarction.

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

– Severe hepatic insufficiency (more than 9 points by Child-Pugh score).

– Sinus node weakness syndrome.

– Sinoatrial block.

– Unstable or acute heart failure.

– Pacemaker dependence (conditions in which the heart rhythm is provided exclusively by the pacemaker).

– Unstable angina.

– Atrioventricular (AV) block of II and III degree.

– Concomitant use with potent cytochrome P4503A4 isoenzyme system inhibitors such as azole group antifungals (ketoconazole, itraconazole), macrolide group antibiotics (clarithromycin, oral erythromycin, jozamicin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see Pharmacokinetics and Interaction with other medicinal products).

– Concurrent use with verapamil or diltiazem, which are moderate CYP3A4 isoenzyme inhibitors with HR-thinning ability (see “Interaction with Other Medicinal Products”).

– Pregnancy, breast-feeding and use in women of childbearing age who do not observe reliable contraception measures (see section “Use in pregnancy and during breast-feeding”).

– Age

Side effects

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

List of adverse reactions

The frequency of adverse reactions that have been reported in clinical trials is given as the following grading: very common (³ 1/10); common (³ 1/100,< 1/10); infrequent (³ 1/1000,< 1/100); rare (³ 1/10000,< 1/1000); very rare (< 1/10000); frequency is unknown (frequency cannot be estimated based on available data).

Nervous system disorders:

often: headache, especially in the first month of therapy, dizziness, possibly associated with bradycardia;

infrequent: fainting, possibly associated with bradycardia.

Visual disorders:

very common: changes in light perception (phosphenes) were noted in 14.5% of patients and described as transient changes in brightness in a limited area of the visual field. As a rule, such phenomena were provoked by an abrupt change in light intensity. Phosphenes may also occur, which may take the form of a halo, disintegration of the visual picture into separate parts (stroboscopic and kaleidoscopic effects), appear as bright color flashes or multiple images (retinal persistence). Photopsia appeared mostly in the first two months of treatment, but could occur repeatedly thereafter. The severity of photopsia was usually mild to moderate. The occurrence of photopsia ceased during continuation of therapy (in 77.5% of cases) or after its completion. In less than 1% of patients, the appearance of photoptysia was the reason for changing their lifestyle or refusing treatment;

often: blurred vision;

infrequent: diplopia, visual disturbance.

Hearing organ and labyrinth disorders:

infrequent: vertigo.

Cardiac disorders:

often: bradycardia in 3.3% of patients, especially during the first 2-3 months of therapy, > 0.5% of patients developed marked bradycardia with HR of 40 bpm or less, grade I AV blockade (prolongation of PQ interval on ECG), ventricular extrasystole, uncontrolled BP changes, atrial fibrillation were observed in 5.3% of patients receiving ivabradine, compared with 3.8% of those receiving placebo. In an analysis of pooled data from clinical trials with a follow-up period of at least 3 months, atrial fibrillation occurred in 4.86% of patients receiving ivabradine compared to 4.08% in control groups;

infrequent: palpitations, supraventricular estrasystole;

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

vascular disorders:

often: marked BP decrease, possibly associated with bradycardia.

Disorders of respiratory system, thorax and mediastinum:

infrequent: shortness of breath.

Gastrointestinal tract disorders:

not often: nausea, constipation, diarrhea, abdominal pain.

Dermal and subcutaneous tissue disorders:

infrequent: skin rash, angioedema;

rarely: erythema, skin itching, urticaria.

Musculoskeletal and connective tissue disorders:

infrequent: muscle spasms.

General disorders and disorders at the site of administration:

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

rare: malaise, possibly associated with bradycardia.

Laboratory and instrumental data:

infrequent: hyperuricemia, eosinophilia, increased plasma creatinine concentration, prolonged QT interval on ECG.

Overdose

Symptoms

Bravadine overdose may cause severe and prolonged bradycardia.

Treatment

The treatment of severe bradycardia is symptomatic and should be done in a specialized hospital setting. If bradycardia is combined with abnormal hemodynamic parameters, the use of beta-adrenomimetics (isoprenaline) is necessary. If necessary – pacemaker implantation.

Pregnancy use

Pregnancy

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

Bravadine is contraindicated for use in pregnancy due to insufficient safety data.

Breastfeeding period

The use of Bravadine during breastfeeding is contraindicated.

It is unknown whether ivabradine penetrates into breast milk.

Breastfeeding should be stopped if Bravadin must be used during lactation.

Similarities