Bravadin (Tablets) Instructions for Use

Marketing Authorization Holder

Krka-Rus, LLC (Russia)

ATC Code

C01EB17 (Ivabradine)

Active Substance

Ivabradine (Rec.INN registered by WHO)

Dosage Forms

	Bravadin	Film-coated tablets, 5 mg: 14, 28, 30, 56, 60, 84, 90 or 98 pcs.
		Film-coated tablets, 7.5 mg: 14, 28, 30, 56, 60, 84, 90 or 98 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pale orange in color, oval, biconvex, with a score on one side; the fracture view is a white rough mass with a pale orange film coating.

Excipients : lactose monohydrate – 64.636 mg, microcrystalline cellulose – 20 mg, povidone K30 – 6 mg, croscarmellose sodium – 2 mg, colloidal silicon dioxide – 0.5 mg, magnesium stearate – 1 mg.

Film coating composition Opadry orange 03H32599 – 3 mg (hypromellose – 71.714%, titanium dioxide (E171) – 15.936%, talc – 6.972%, propylene glycol – 4.98%, iron oxide yellow (E172) – 0.332%, iron oxide red (E172) – 0.066%).

14 pcs. – blister packs (1) – cardboard boxes.
14 pcs. – blister packs (2) – cardboard boxes.
14 pcs. – blister packs (4) – cardboard boxes.
14 pcs. – blister packs (6) – cardboard boxes.
14 pcs. – blister packs (7) – cardboard boxes.
15 pcs. – blister packs (2) – cardboard boxes.
15 pcs. – blister packs (4) – cardboard boxes.
15 pcs. – blister packs (6) – cardboard boxes.

Film-coated tablets pale orange in color, round, slightly biconvex, with a bevel; the fracture view is a white rough mass with a pale orange film coating.

Excipients : lactose monohydrate – 96.954 mg, microcrystalline cellulose – 30 mg, povidone K30 – 9 mg, croscarmellose sodium – 3 mg, colloidal silicon dioxide – 0.75 mg, magnesium stearate – 1.5 mg.

Film coating composition Opadry orange 03H32599 – 4.5 mg (hypromellose – 71.714%, titanium dioxide (E171) – 15.936%, talc – 6.972%, propylene glycol – 4.98%, iron oxide yellow (E172) – 0.332%, iron oxide red (E172) – 0.066%).

14 pcs. – blister packs (1) – cardboard boxes.
14 pcs. – blister packs (2) – cardboard boxes.
14 pcs. – blister packs (4) – cardboard boxes.
14 pcs. – blister packs (6) – cardboard boxes.
14 pcs. – blister packs (7) – cardboard boxes.
15 pcs. – blister packs (2) – cardboard boxes.
15 pcs. – blister packs (4) – cardboard boxes.
15 pcs. – blister packs (6) – cardboard boxes.

Clinical-Pharmacological Group

Selective inhibitor of If-channels of the sinus node, regulating heart rate

Pharmacotherapeutic Group

Anti-anginal agent

Pharmacological Action

Anti-anginal agent. The mechanism of action consists in the selective and specific inhibition of the If channels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate heart rate.

Ivabradine has a selective effect on the sinus node, without affecting the impulse conduction time through the intra-atrial, atrioventricular and intraventricular conduction pathways, as well as myocardial contractility and ventricular repolarization.

The main pharmacodynamic property of ivabradine is a specific, dose-dependent reduction in heart rate. Analysis of the magnitude of heart rate reduction at doses above 20 mg twice daily revealed a tendency to reach a plateau effect, which reduces the risk of developing severe, poorly tolerated bradycardia (heart rate less than 40 beats/min).

When used at recommended doses, the reduction in heart rate is approximately 10-15 beats/min at rest and during physical exertion. As a result, the work of the heart is reduced and the myocardial oxygen demand is decreased.

Ivabradine is also capable of interacting with the retinal Ih channels, which are similar to the cardiac If channels. The Ih channel is involved in the occurrence of temporary changes in the resolution of the visual system, as it reduces the retinal response to bright light stimuli. Under provoking circumstances (for example, rapid changes in brightness), Ivabradine partially inhibits the Ih electrical impulse, which sometimes in some patients leads to the occurrence of light sensations (phosphènes), described as a brief sensation of increased brightness in a limited part of the visual field.

Against the background of ivabradine use in patients with CHF functional class II-IV according to the NYHA classification with LVEF less than 35%, a clinically and statistically significant reduction in the relative risk of complications (frequency of fatal outcomes from cardiovascular diseases and reduction in the frequency of hospitalizations due to worsening of CHF symptoms) by 18% was shown. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed after 3 months from the start of therapy.

Pharmacokinetics

The pharmacokinetics of ivabradine in doses from 0.5 to 24 mg is linear.

After oral administration, Ivabradine is rapidly and almost completely absorbed from the gastrointestinal tract. C_max in plasma is reached approximately 1 hour after oral administration on an empty stomach. Bioavailability is approximately 40%, which is due to the first-pass effect through the liver. Food intake increases the absorption time by approximately 1 hour and increases plasma concentration by 20-30%. Plasma protein binding is about 70%. V_d is about 100 L. C_ss^max in plasma after long-term use at the recommended dose of 5 mg twice daily is approximately 20 ng/ml (CV=29%). The average C_ss in plasma is 10 ng/ml (CV=38%).

Ivabradine is extensively metabolized in the liver and intestine by oxidation in the presence of the CYP3A4 isoenzyme. The main active metabolite is the N-desmethylated derivative (S18982), its share is 40% of the dose of the parent compound. The metabolism of the active metabolite of ivabradine also occurs in the presence of the CYP3A4 isoenzyme.

T_1/2 of ivabradine is 2 hours (70-75% AUC) and the effective T_1/2 is 11 hours. Total clearance is approximately 400 ml/min, renal clearance is about 70 ml/min. Excretion of metabolites occurs at the same rate in urine and feces. About 4% of the orally administered dose is excreted unchanged in the urine.

In patients with renal insufficiency (CrCl 15-60 ml/min), changes in pharmacokinetic parameters are minimal due to the low participation of renal clearance (about 20%) in the total elimination of ivabradine and its main metabolite S18982.

In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale), the AUC of ivabradine and its active metabolite is 20% greater than with normal liver function.

Indications

Treatment of stable angina pectoris in patients with normal sinus rhythm: in case of intolerance or contraindications to the use of beta-blockers; in combination with beta-blockers in case of inadequate control of stable angina pectoris against the background of an optimal dose of a beta-blocker.

Chronic heart failure: to reduce the incidence of cardiovascular complications in patients with chronic heart failure, with sinus rhythm and heart rate of at least 70 beats/min.

ICD codes

Dosage Regimen

The average recommended initial dose of ivabradine is 5 mg twice daily (10 mg/day). Depending on the therapeutic effect after 3-4 weeks of use, the dose can be increased to 7.5 mg twice daily (15 mg/day).

If during therapy the heart rate decreases to values less than 50 beats/min or symptoms associated with bradycardia occur (such as dizziness, fatigue or arterial hypotension), a lower dose should be selected; if necessary, the dose can be reduced to 2.5 mg twice daily. If the heart rate remains less than 50 beats/min and the symptoms of bradycardia do not resolve, then treatment should be discontinued.

In elderly patients, it is recommended to start treatment with an initial dose of 2.5 mg twice daily. Subsequently, an increase in the daily dose is possible depending on the patient’s condition.

Adverse Reactions

Sensory organs very common – visual brightness (photopsia); common – blurred vision; uncommon – vertigo; frequency not specified – diplopia, visual impairment.

Cardiovascular system common – bradycardia, first-degree AV block, ventricular extrasystole, transient increase in blood pressure; uncommon – palpitations, supraventricular extrasystole; very rare – atrial fibrillation, second- and third-degree AV block, sick sinus syndrome; frequency not specified – marked decrease in blood pressure, possibly associated with bradycardia.

Digestive system uncommon – nausea, constipation, diarrhea.

CNS: common – headache (especially during the first month of therapy), dizziness, possibly associated with bradycardia; frequency not specified – syncope, possibly associated with bradycardia.

Respiratory system uncommon – dyspnea.

Contraindications

Bradycardia (resting heart rate below 60 beats/min before starting treatment); cardiogenic shock; acute myocardial infarction; severe arterial hypotension (systolic blood pressure below 90 mm Hg and diastolic blood pressure below 50 mm Hg); severe hepatic impairment (more than 9 points on the Child-Pugh scale); sick sinus syndrome; sinoatrial block; chronic heart failure functional class III and IV according to the NYHA classification; presence of a pacemaker operating in constant stimulation mode; unstable angina; third-degree AV block; pregnancy; lactation (breastfeeding); children and adolescents under 18 years of age; simultaneous 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; hypersensitivity to ivabradine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment. Should be used with caution in patients with moderate hepatic impairment.

Use in Renal Impairment

Should be used with caution in patients with CrCl below 15 ml/min.

Pediatric Use

Not recommended for use in children and adolescents under 18 years of age.

Special Precautions

Use with caution in moderate hepatic impairment (less than 9 points on the Child-Pugh scale); severe renal failure (CrCl<15 ml/min); congenital long QT syndrome; simultaneously with the use of drugs that prolong the QT interval (risk of developing severe ventricular arrhythmia of the "torsades de pointes" type); simultaneously with the use of moderate inhibitors and inducers of CYP3A4 isoenzymes and grapefruit juice; with second-degree AV block; recently suffered stroke; retinitis pigmentosa; arterial hypotension; chronic heart failure functional class IV according to the NYHA classification; simultaneously with the use of heart rate-lowering slow calcium channel blockers, such as verapamil or diltiazem; simultaneously with the use of non-potassium-sparing diuretics.

Ivabradine is not effective for the treatment or prevention of arrhythmias. Its effectiveness decreases against the background of the development of tachyarrhythmia (for example, ventricular or supraventricular paroxysmal tachycardia).

Not recommended for use in patients with atrial fibrillation or other types of arrhythmias associated with sinus node function.

During therapy with ivabradine, it is recommended to regularly monitor the patient’s condition for the development of atrial fibrillation (paroxysmal or permanent ) . If clinically indicated (for example, worsening of angina, palpitations, irregular heart rhythm), ECG should be regularly monitored.

The risk of developing atrial fibrillation may be higher in patients with chronic heart failure taking Ivabradine. Atrial fibrillation was more common among patients who were taking amiodarone or class I antiarrhythmic drugs simultaneously with ivabradine.

Before deciding on the use of ivabradine, the course of heart failure must be stable. Patients with chronic heart failure and intraventricular conduction disorders (left or right bundle branch block) and ventricular dyssynchrony require constant medical supervision.

No increase in the risk of severe bradycardia has been proven against the background of ivabradine intake during restoration of sinus rhythm during pharmacological cardioversion. Nevertheless, due to the lack of sufficient data, if it is possible to postpone planned electrical cardioversion, ivabradine intake should be discontinued 24 hours before its implementation.

Reduction of heart rate due to ivabradine intake may exacerbate the prolongation of the QT interval, which, in turn, may provoke the development of a severe form of arrhythmia, in particular, polymorphic ventricular tachycardia of the "torsades de pointes" type.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, the patient should exercise caution when engaging in potentially hazardous activities that require high speed of psychomotor reactions in situations where sudden changes in illumination may occur, especially at night.

Drug Interactions

When used concomitantly with ivabradine of drugs that increase the QT interval (quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin), an enhancement of heart rate reduction and additional prolongation of the QT interval is possible. If simultaneous therapy is necessary, ECG parameters should be carefully monitored (such combinations are not recommended).

Ivabradine is metabolized in the liver with the participation of the CYP3A4 isoenzyme and is a very weak inhibitor of this isoenzyme. Ivabradine does not significantly affect the metabolism and plasma concentration of other substrates (strong, moderate and weak inhibitors) of cytochrome CYP3A4. At the same time, inhibitors and inducers of the CYP3A4 isoenzyme can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It has been established that inhibitors of the CYP3A4 isoenzyme increase, and inducers of the CYP3A4 isoenzyme decrease the plasma concentrations of ivabradine. An increase in the plasma concentration of ivabradine may increase the risk of developing severe bradycardia.

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, nefazodone) is contraindicated due to an increase in the plasma concentration of ivabradine and the risk of excessive bradycardia.

Concomitant use of ivabradine and moderate inhibitors of the CYP3A4 isoenzyme diltiazem or verapamil (heart rate-lowering agents) in healthy volunteers and patients was accompanied by an increase in the AUC of ivabradine by 2-3 times and an additional reduction in heart rate by 5 beats/min. These combinations are not recommended.

Inducers of the CYP3A4 isoenzyme, such as rifampicin, barbiturates, phenytoin and herbal preparations containing St. John’s wort (Hypericum perforatum), when used concomitantly with ivabradine, may lead to a decrease in the blood concentration and activity of ivabradine (it may be necessary to use the drug at a higher dose). When ivabradine and preparations containing St. John’s wort were used concomitantly, a twofold decrease in the AUC of ivabradine was noted. During the use of ivabradine, the intake of herbal preparations containing St. John’s wort should be reduced.

Use of ivabradine in combination with other moderate inhibitors of the CYP3A4 isoenzyme (for example, fluconazole) is possible provided that the resting heart rate is more than 60 beats/min. The recommended initial dose of ivabradine is 2.5 mg twice daily. Heart rate monitoring is necessary.

Ivabradine should be used with caution with non-potassium-sparing diuretics (thiazide and "loop" diuretics), as hypokalemia may increase the risk of arrhythmia. Since Ivabradine can cause bradycardia, the combination of hypokalemia and bradycardia is a predisposing factor for the development of a severe form of arrhythmia, especially in patients with long QT syndrome, both congenital and caused by exposure to any substances.

When consuming grapefruit juice against the background of ivabradine use, an increase in the blood concentration of ivabradine by 2 times was noted. During therapy with ivabradine, the intake of grapefruit juice should be reduced.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.