Ivabradin

Brand Gedeon Richter

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Available since: 2019-09-19

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Clinical Pharmacology

Ivabradine is a drug that slows the rhythm of the heart, the mechanism of action of which is the selective and specific inhibition of the If-channels of the sinus node, controlling spontaneous diastolic depolarization in the sinus node and regulating heart rate. 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.

Indications

Stable angina in patients with normal sinus rhythm with intolerance or contraindications to the use of beta-blockers

Composition

Active ingredient: ivabradine hydrobromide - 8.795 mg (equivalent to ivabradine 7.5 mg).

Excipients: lactose - 41.675 mg, mannitol - 44.530 mg, maltodextrin - 3.000 mg, croscarmellose sodium - 1.000 mg, silicon dioxide, colloidal - 0.500 mg, magnesium stearate - 0.500 mg.

Tablet shell: Opadra pink - 3,000 mg (contains: polyvinyl alcohol -1.050 mg, talc - 0.716 mg, titanium dioxide - 0.705 mg, macrogol-3350 - 0.360 mg, methacrylic acid copolymer (type C) - 0.120 mg, iron dye yellow oxide -0.038 mg, iron dye red oxide - 0.007 mg, sodium bicarbonate - 0.004 mg).

Ivabradin is marketed under different brands and generic names, and comes in different dosage forms:

Brand name	Manufacturer	Country	Dosage form
Raen	Gedeon Richter	Hungary	pills
Bravadin	Krka dd Novo mesto AO	Slovenia	pills
Coraxan	Servier	France	pills

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Dosage and Administration

Orally, 2 times a day (in the morning and in the evening), during food.
The initial recommended daily dose is 10 mg per day (5 mg 2 times a day). Depending on the therapeutic effect, after 3–4 weeks, the daily dose may be increased to 15 mg (7.5 mg twice a day). If heart rate drops below 50 / min during therapy or symptoms associated with bradycardia (dizziness, fatigue or a decrease in blood pressure) occur, a lower dose of the drug should be used. If the heart rate does not return to normal when the dose is reduced and less than 50 / min remains, the drug is canceled. In elderly patients, treatment should be started with an initial dose of 2.5 mg (1/2 tablet 5 mg) 2 times a day; may increase the daily dose depending on the condition of the patient.

Adverse reactions

On the part of the organ of vision: very often - 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 zone 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 2 months of treatment, followed by repetition. The severity of photopsia, as a rule, was mild or moderate. The appearance of the photopsia was stopped on the background of continuing therapy (77.5% of cases) or after its completion. In less than 1% of patients, photopsy was the reason for refusing treatment. Often - blurred vision.
On the part of the cardiovascular system: often - bradycardia (3.3% of patients, especially in the first 2-3 months of therapy, 0.5% of patients developed severe bradycardia with a heart rate of not more than 40 beats / min); AV blockade I degree; ventricular premature beats; infrequently - palpitations, supraventricular extrasystole; unspecified frequency - hypotension, possibly associated with bradycardia; the following adverse events identified in clinical trials occurred with the same frequency in both the group of patients receiving ivabradine and the comparison group, which suggests their connection with the disease as such, and not with taking ivabradine - sinus arrhythmia; angina pectoris, incl. unstable; atrial fibrillation; myocardial ischemia; myocardial infarction and ventricular tachycardia.
On the part of the digestive system: rarely - nausea, constipation, diarrhea.
From the side of the central nervous system: often - headache, especially in the first month of therapy; dizziness, possibly associated with bradycardia; infrequently - shortness of breath, vertigo, muscle spasms; unspecified frequency - syncope, possibly associated with bradycardia.
Laboratory indicators: infrequently - hyperuricemia, eosinophilia, increased plasma creatinine concentration.
On the part of the skin and subcutaneous fat: unspecified frequency - skin rash, pruritus, erythema, angioedema, urticaria.
Common disorders and symptoms: unspecified frequency - asthenia; increased fatigue; malaise, possibly related to bradycardia.

Contraindications

Hypersensitivity, resting heart rate below 60 / min (before 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 failure (more than 9 according to the Child-Pyuga classification), SSSU, SA-blockade, CHF III-IV Art. (according to NYHA classification - lack of clinical experience), artificial pacemaker, unstable stenocardia, AV-blockade of stage II-III, acute cerebrovascular accident, simultaneous use of strong inhibitors of cytochrome P450 CYP3A4 (including ketoconazole, itraconazole, clarithromycin, erythromycin, josamycin, telithromycin, nelfinavir, ritonavir, nefazodone); galactose intolerance, lactase deficiency, glucose-galactose deficiency (for LF containing lactose), pregnancy, lactation period, age under 18 years (efficacy and safety have not been established).

Drug interactions

Unwanted combinations

Drugs that extend 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, sertindol, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for intravenous administration).

The simultaneous use of ivabradine and these drugs should be avoided, since a decrease in heart rate may cause an additional lengthening of the QT interval. If necessary, the simultaneous use of these drugs should be carefully monitored ECG.

CYP3A4 isoenzyme

Ivabradine is metabolized in the liver with the participation of the CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. Ivabradine has no significant effect on the metabolism and plasma concentration of other substrates (potent, moderate and weak inhibitors) of the CYP3A4 isoenzyme. 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 was found that CYP3A4 isoenzyme inhibitors increase, and CYP3A4 isoenzyme inducers reduce the concentration of ivabradine in the blood plasma.

Increasing plasma plasma concentrations of ivabradine may increase the risk of developing bradycardia.

Contraindications

Potent inhibitors of the isoenzyme CYP3A4

The simultaneous use of ivabradine with potent inhibitors of the CYP3A4 isoenzyme, such as antifungal agents of the azole group (ketoconazole, itraconazole); macrolide antibiotics (clarithromycin, oral intake, erythromycin, josamycin, telithromycin); HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone are contraindicated. Potent inhibitors of CYP3A4 isoenzyme - ketoconazole (200 mg 1 time / day) or josamycin (1 g 2 times / day) - increase the average plasma concentrations of ivabradine in 7-8 times.

Moderate inhibitors of isoenzyme CYP3A4

Simultaneous use of ivabradine and diltiazem or verapamil (drugs that slow heart rate) in healthy volunteers and patients was accompanied by an increase in AUC of ivabradine by a factor of 2-3 and an additional decrease in heart rate by 5 beats / min. The use of these combinations is contraindicated.

Combinations that require caution

The use of ivabradine in combination with other moderate inhibitors of the CYP3A4 isoenzyme (for example, fluconazole) is possible provided that the heart rate at rest is more than 60 beats / min. The recommended initial dose of ivabradine is 2.5 mg 2 times / day. Heart rate control is required.

Simultaneous use with CYP3A4 isoenzyme inducers, such as rifampicin, barbiturates, phenytoin, and herbal remedies containing Hypericum perforatum (Hypericum perforatum), can lead to a decrease in plasma concentration and ivabradine activity and require a higher dose of ivabradine. With the joint use of ivabradine and preparations containing St. John's wort, it was noted a twofold decrease in the AUC of ivabradine. During the period of drug therapy Raen^® as far as possible avoid the use of drugs and products containing St. John's wort.

It is necessary to use the drug with caution simultaneously with potassium-sparing diuretics (diuretics of the thiazide group and "loop" diuretics), since hypokalemia may increase the risk of arrhythmia. Since Ivabradine can cause bradycardia, a combination of hypokalemia and bradycardia is a predisposing factor for the development of a severe form of arrhythmia, especially in patients with the syndrome of lengthening the QT interval, both congenital and caused by exposure to any substances.

Combined use with other drugs

The absence of a clinically significant effect on the pharmacodynamics and pharmacokinetics of Ivabradine with the simultaneous use of the following drugs: proton pump inhibitors (omeprazole, lansoprazole), PDE5 inhibitors (for example, sildenafil), HMG-CoA reductase inhibitors (for example, simvastatin), BMKK - series (for example, amlodipine, lacidipine), digoxin and warfarin. Ivabradine has not been shown to 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.

Ivabradine used in combination with ACE inhibitors, angiotensin II receptor, beta-blockers, diuretics, aldosterone antagonists, nitrates short and long-acting inhibitors of HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, hypoglycemic agents for oral administration, acetylsalicylic acid and other antiplatelet agents. The use of the above medicines was not accompanied by a change in the safety profile of the therapy.

Other interactions requiring caution when used together

While taking grapefruit juice, a twofold increase in plasma concentration of ivabradine was observed. During the period of drug therapy Raen^® whenever possible, avoid using grapefruit juice.

Special instructions

Heart rhythm disorder

Ivabradine is ineffective in treating or preventing arrhythmias. Its effectiveness decreases with the development of tachyarrhythmias (for example, ventricular or supraventricular tachycardia). Drug Raen^® not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function.

During therapy with Raen^® Clinical monitoring of patients for atrial fibrillation should be carried out (paroxysmal or permanent). According to clinical indications (for example, worsening of the course of stenocardia, the appearance of a sensation of heartbeat, irregular heart rhythm), an ECG should be included in the current control.

The risk of developing atrial fibrillation may be higher in patients with CHF who take Raen^®. Atrial fibrillation was more common among patients who took amiodarone or class I antiarrhythmic drugs simultaneously with ivabradine. Patients with CHF and impaired intraventricular conduction (blockade of the left or right leg of the bundle of His) and ventricular dyssynchrony should be controlled.

Use in patients with bradycardia

Ivabradine is contraindicated if, before initiating therapy, the heart rate at rest is less than 60 beats / min. If, during therapy, the heart rate diminishes to less than 50 bpm / min, or the patient has symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), the dose should be reduced. If, at lower doses of the drug, the heart rate remains less than 50 beats / min or symptoms associated with bradycardia persist, then the intake of the drug Raen^® should stop.

Combined use as part of antianginal therapy

Use of the drug Raen^® in conjunction with BMCC, reducing heart rate, such as verapamil or diltiazem, is contraindicated. With the combined use of ivabradine with nitrates and BCCA, derivatives of the dihydropyridine series, such as amlodipine, no changes in the safety profile of the therapy were observed. It is not established that the combined use with BMKK increases the effectiveness of ivabradine.

Stroke

It is not recommended to prescribe the drug Raen^® immediately after a stroke, because data on the use of the drug in this period are not available.

Visual Perception Functions

Ivabradine affects the function of the retina. To date, no toxic effects of ivabradine on the retina have been identified. However, there are no data on the effect of ivabradine on the retina with prolonged use (more than 1 year). If a violation of the visual functions that are not described in this manual occurs, consider discontinuing Raen^®. Patients with retinal pigment degeneration (retinitis pigmentosa) drug Raen^® should be taken with caution.

Hypotension

Raen^® should be used with caution in patients with arterial hypotension (due to insufficient clinical data).

Raen^® contraindicated in severe hypotension (systolic blood pressure less than 90 mm Hg. Art. and diastolic blood pressure less than 50 mm Hg. Art.).

Atrial fibrillation (atrial fibrillation) - cardiac arrhythmias

An increase in the risk of developing severe bradycardia during the use of ivabradine during pharmacological cardioversion with the aim of restoring sinus rhythm has not been proven. However, due to insufficient data, if possible, to delay the planned electrical cardioversion, taking the drug Raen^® should stop 24 hours in advance.

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

Drug Raen^® should not be used for congenital long QT syndrome, as well as in combination with drugs that can prolong the QT interval. If necessary, the simultaneous use of such drugs requires strict ECG monitoring. Decrease in heart rate due to the use of the drug Raen^®may aggravate the prolongation of the QT interval, which, in turn, may trigger the development of a severe form of arrhythmia, in particular, polymorphic ventricular tachycardia of the "pirouette" type.

Hypertensive patients requiring a switch to another antihypertensive drug

When changing antihypertensive therapy in patients with CHF taking the drug Raen^®, monitoring of blood pressure is required at appropriate intervals.

Chronic heart failure

Before deciding on the use of the drug Raen^® heart failure should be stable. Caution must be exercised when using the drug Raen.^® in patients with chronic heart failure IV functional class according to the NYHA classification due to limited data on the use of the drug in this category of patients.

Hepatic insufficiency moderate

With moderately severe liver failure (less than 9 points on the Child-Pugh scale), therapy with Raen^® should be done with caution.

Severe renal failure

In case of severe renal failure (CC less than 15 ml / min) Raen's therapy^® should be done with caution.

Excipients

Drug Raen^® contains lactose, therefore it is not recommended for patients with lactase deficiency, lactose intolerance and glucose / galactose malabsorption syndrome.

Influence on ability to drive motor transport and control mechanisms

Ivabradine does not affect the ability to drive vehicles and perform work that requires high-speed psychomotor reactions. However, you should remember about the possibility of photopsy with a sharp change in the intensity of illumination, especially when driving at night.