Coraxan, pills 5mg, 56pcs

Composition

1 tablet of 5 mg contains:

Active ingredient:

ivabradine hydrochloride is 5.39 mg, which corresponds to 5.0 mg of the base.

Auxiliary substances:

lactose monohydrate 63.91 mg,

magnesium stearate 0.5 mg,

corn starch 20 mg,

maltodextrin 10 mg,

colloidal anhydrous silicon dioxide 0.20 mg.

Shell:

glycerol 0.08740 mg,

hypromellose 1.45276 mg,

iron oxide yellow dye (E172) 0.01457 mg,

iron oxide red dye (E172) 0.00485 mg,

macrogol 6000 0.09276 mg,

magnesium stearate 0.08740 mg,

titanium dioxide (e171) 0.26026 mg

Pharmacological action

Ivabradine is a drug that slows the heart rate, the mechanism of action of which is to selectively and specifically inhibit the I_-fchannels of the sinus node, which control spontaneous diastolic depolarization in the sinus node and regulate the heart rate (HR). Ivabradine has a selective effect on the sinus node, without affecting the time of impulses along the intra-atrial, atrioventricular and intraventricular pathways, as well as the contractility of the myocardium 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 the occurrence of temporary changes in the visual perception system due to changes in the retinal response to bright light stimuli.

Under provoking circumstances (for example, a rapid change in brightness in the visual field), partial inhibition of ihchannels by ivabradine causes the phenomenon of changing light perception (photopsia). Photopsy is characterized by a transient change in brightness in a limited area of the visual field (see the section “Side effect”). The main pharmacological feature of ivabradine is the ability to reduce the dose-dependent heart rate (HR). The analysis of the dependence of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg twice a day and revealed a tendency to achieve a “plateau” effect (no increase in the therapeutic effect with a further increase in the dose), which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min) (see azdel “Side effect”).

When prescribing the drug in the recommended doses, the degree of heart rate reduction depends on its initial value and is approximately 10-15 beats / min at rest and during physical exertion. As a result, the work of the heart decreases and the need for oxygen in the myocardium decreases.

Ivabradine does not affect intracardiac conduction, myocardial contractility (does not cause a negative inotropic effect) and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine did not affect the timing of impulses along the atrioventricular or intraventricular pathways, as well as the adjusted QT intervals. In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%), ivabradine has not been shown to affect myocardial contractility.

It was found that ivabradine at a dose of 5 mg 2 times a day improved the performance of exercise tests after 3-4 weeks of therapy. The effectiveness was also confirmed for a dose of 7.5 mg 2 times a day. In particular, the additional effect of increasing the dose from 5 to 7.5 mg 2 times a day was established in a comparative study with atenolol. The time to perform physical activity increased by approximately 1 minute after 1 month of ivabradine 5 mg 2 times a day, while after an additional 3-month course of ivabradine 7.5 mg 2 times a day orally, a further increase in this indicator by 25 seconds was noted. The anti-anginal and anti-ischemic activity of ivabradine was also confirmed for patients aged 65 years and older. The efficacy of ivabradine at doses of 5 mg and 7.5 mg 2 times a day was observed for all indicators of exercise tests (total duration of physical activity, time to limiting angina attack, time to the onset of angina attack and time to the development of ST segment depression by 1 mm), and was accompanied by a decrease in the frequency of angina attacks by approximately 70%. The use of ivabradine 2 times a day provided constant therapeutic efficacy for 24 hours.

In patients treated with ivabradine, ivabradine was shown to be more effective in relation to all indicators of exercise tests when added to the maximum dose of atenolol (50 mg) at the decline of therapeutic activity (12 hours after oral use). No improvement in ivabradine efficacy was shown when added to the maximum dose of amlodipine at the decline in therapeutic activity (12 hours after oral use), while at the maximum activity (3 to 4 hours after oral use), the additional effectiveness of ivabradine was proven.

In studies of the clinical efficacy of the drug, the effects of ivabradine were completely preserved during the 3 – and 4-month treatment periods. During treatment, there were no signs of developing tolerance (reduced effectiveness), and after discontinuation of treatment, there was no “withdrawal” syndrome. The anti-anginal and anti-ischemic effects of ivabradine were associated with a dose-dependent reduction in heart rate, as well as with a significant decrease in the work product (heart rate × systolic blood pressure), both at rest and during exercise. The effect on blood pressure (BP) and total peripheral vascular resistance (OPSS) was insignificant and clinically insignificant.

A steady decrease in heart rate was observed in patients taking ivabradine for at least 1 year. No effect on carbohydrate metabolism and lipid profile was observed.

In patients with diabetes mellitus, the efficacy and safety indicators of ivabradine were similar to those in the general patient population.

There were no differences between the groups of patients taking ivabradine to standard therapy, and in patients with stable angina and left ventricular dysfunction (FVLI less than 40%),86.9% of whom received beta-blockers and placebo, the total frequency of deaths from cardiovascular disease, hospitalization for acute myocardial infarction, hospitalization for about the emergence of new cases of heart failure, or exacerbate symptoms of chronic heart failure (CHF) and in the subgroup of patients with heart rate of at least 70 beats/min.

Against the background of ivabradine use in patients with a heart rate of at least 70 beats/min. A 36% reduction in the frequency of hospitalizations for fatal and non-fatal myocardial infarction and a 30% reduction in the frequency of revascularization was shown.

Patients with exertional angina while taking ivabradine showed a 24% reduction in the relative risk of complications (the frequency of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or increased symptoms of CHF). The noted therapeutic advantage is achieved primarily by reducing the frequency of hospitalization for acute myocardial infarction by 42%. The reduction in the frequency of hospitalization for fatal and non-fatal myocardial infarction in patients with a heart rate of more than 70 beats / min is even more significant and reaches 73%. In general, good tolerability and safety of the drug were noted.

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

A decrease in mortality from cardiovascular diseases and a decrease in the frequency of hospitalizations due to increased symptoms of CHF were observed regardless of age, gender, functional class of CHF, use of beta-blockers, ischemic or non-ischemic etiology of CHF, the presence of diabetes mellitus or arterial hypertension in the anamnesis.

Patients with symptoms of CHF with sinus rhythm and a heart rate of at least 70 beats / min received standard therapy, including the use of beta-blockers (89%), angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor antagonists (91%), diuretics (83%), and aldosterone antagonists (60%).

It has been shown that the use of ivabradine for 1 year can prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug. Against the background of ivabradine use, an improvement in the functional class of CHF according to the NYHA classification was shown.

In patients with a heart rate of 80 beats / min, a decrease in heart rate by an average of 15 beats/min was noted.

Ivabradine is an S-enantiomer, with no bioconversion according to in vivo studies. The main active metabolite of the drug is the N-desmethylated derivative of ivabradine.

Absorption and bioavailability

Ivabradine is rapidly and almost completely absorbed in the gastrointestinal tract after oral use. The maximum concentration (cmax ) in blood plasma is reached approximately 1 hour after ingestion on an empty stomach.Bioavailability is approximately 40%, due to the “first pass” effect through the liver.

Food intake increases the absorption time by approximately 1 hour and increases the plasma concentration from 20% to 30%. To reduce the variability in the concentration of the drug, it is recommended to take it simultaneously with a meal (see the section “Dosage and use”).

Distribution

The binding to plasma proteins is approximately 70%. The volume of distribution at steady state is about 100 l. Cmax in blood plasma after prolonged use at the recommended dose of 5 mg 2 times a day is approximately 22 ng / ml (coefficient of variation = 29%). The average steady-state plasma concentration is 10 ng / ml (coefficient of variation=38%).

Metabolism Ivabradine is largely metabolized in the liver and intestines by oxidation involving only cytochrome P4503A4 (the CYP3A4 isoenzyme). The main active metabolite is the N-desmethylated derivative (S 18982), which accounts for 40% of the dose concentration of ivabradine. The active metabolite of ivabradine is also metabolized in the presence of the CYP3A4 isoenzyme. Ivabradine has a low affinity for the CYP3A4 isoenzyme, does not induce or inhibit it. Therefore, it is unlikely that ivabradine affects the metabolism or concentration of substrates of the CYP3A4 isoenzyme in blood plasma. On the other hand, concomitant use of potent cytochrome P450 inhibitors or inducers may significantly affect the plasma concentrations of ivabradine (see sections “Interactions with other medicinal products” and “Special Instructions”).

Deduction

The elimination half-life (T_1/2 ) of ivabradine is, on average,2 hours (70-75% of the area under the concentration – time curve (AUC)), the effective T_1/2 is 11 hours. Total clearance is approximately 400 ml/min, renal clearance is approximately 70 ml/min. Elimination of metabolites occurs at the same rate through the kidneys and intestines. About 4% of the dose taken is excreted unchanged by the kidneys.

Linearity and non-linearity

The pharmacokinetics of ivabradine are linear in the dose range from 0.5 to 24 mg.

Indications

Stable angina Therapy for stable angina 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 against the background of optimal dose of beta-blocker

Chronic heart nedostatochnosti reduce the incidence of cardiovascular complications (mortality from cardiovascular disease and hospitalization in connection with the increased symptoms of CHF) in patients with chronic heart failure with sinus rhythm and heart rate of at least 70 beats/min.

Use during pregnancy and lactation

The drug Coraxan is contraindicated for use during pregnancy. Currently, there is insufficient data on the use of the drug during pregnancy. Preclinical studies of ivabradine revealed embryotoxic and teratogenic effects.

The use of Coraxan during breast-feeding is contraindicated. There is no information about the penetration of ivabradine into breast milk.

Contraindications

• Hypersensitivity to ivabradine or any of the Coraxan excipients;
• Bradycardia (heart rate at rest of less than 60 beats/min (before treatment));
• cardiogenic shock;
• acute myocardial infarction;
• severe hypotension (systolic BP less than 90 mm Hg. St. and diastolic blood pressure less than 50 mm Hg. St. )
• severe liver failure (more than 9 points on a scale child-Pugh);
• syndrome of weakness of the sinus node;
• sinoatrial blockade;
• the presence of an artificial pacemaker;
• unstable angina;
• atrioventricular (AV) blockade of III degree;
• concomitant use of potent inhibitors of isoenzymes of cytochrome P450 3 A 4, such as antifungal agents of the group of azoles (ketoconazole, Itraconazole), the macrolide antibiotics (clarithromycin, erythromycin for oral use, josamycin, telithromycin), an HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone;
• pregnancy and breast-feeding period;
• the age of 18 years (efficacy and safety of the drug in this age group have not been studied);
• lactase deficiency, lactose intolerance, a syndrome of glucose-galactose malabsorption.

With caution:Moderate hepatic insufficiency (less than 9 points on the Child-Pugh scale); severe renal insufficiency (creatinine clearance less than 15 ml/min); congenital prolongation of the QT interval (see the section “Interaction with other drugs”); concomitant use of drugs that prolong the QT interval; concomitant use of moderate inhibitors of cytochrome CYP3A4 isoenzymes and grapefruit juice; asymptomatic left ventricular dysfunction; atrioventricular block II degree retinitis pigmentosa (retinitis pigmentosa); hypotension; concomitant use with slow calcium channel blockers (BCCs) that reduce heart rate, such as verapamil or diltiazem.

Side effects

From the side of the visual organ:Very common: changes in light perception (photopsia): It was observed 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 area of the visual field. Mostly, photopsia appeared in the first two months of treatment with subsequent recurrence. The severity of photopsia was usually mild or moderate. The appearance of photopsia stopped during the continuation of therapy (in 77.5% of cases) or after its completion. In less than 1% of patients, the appearance of photopsia was the reason for refusal of treatment. Often: blurred vision.

From 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 no more than 40 beats / min; AV block of the first degree; ventricular extrasystole. Infrequently: palpitation, supraventricular extrasystole. Unspecified frequency: arterial hypotension, possibly related to bradycardiathe following adverse events identified in clinical studies occurred with the same frequency in both the ivabradine-treated group and the comparison group, which suggests that they are related to the disease itself, and not to ivabradine use: sinus arrhythmia; angina pectoris, including unstable angina pectoris;  atrial fibrillation; myocardial ischemia; myocardial infarction and ventricular tachycardia.

From the digestive system: infrequently: nausea, constipation, diarrhea.

From the central nervous system:Common: headache, especially in the first month of therapy; dizziness, possibly related to bradycardia. Infrequently: shortness of breath, vertigo, muscle spasms. Unspecified frequency: syncope, possibly associated with bradycardia.

Laboratory parameters: infrequently: hyperuricemia, eosinophilia, increased plasma creatinine.

From the skin and subcutaneous fat: skin rash, pruritus, erythema, angioedema, urticaria.

Common disorders and symptoms: asthenia, increased fatigue, malaise, possibly related to bradycardia.

Interaction

Pharmacodynamic interaction

Not recommended combinations

of drugs that prolong the QT interval (for example, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).

DRUGS that prolong the QT interval that are not related to cardiovascular drugs (for example, pimozide, ziprasidone, sertindol, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).

Concomitant use with drugs that prolong the QT interval may increase the decrease in heart rate, so if necessary, co-use should be carefully monitored.

Pharmacokinetic interaction of

Cytochrome P4503A4 (CYP3A4). Ivabradine is metabolized in the liver by cytochrome P450 (CYP3A4) enzymes and is a very weak inhibitor of this cytochrome. Ivabradine does not significantly affect the metabolism and plasma concentrations of other cytochrome CYP3A4 substrates. At the same time, inhibitors and inducers of CYP3A4 interact with ivabradine and affect its metabolism and pharmacokinetic properties. Cytochrome CYP3A4 inhibitors were found to increase and cytochrome CYP3A4 inducers to decrease plasma concentrations of ivabradine. An increase in the concentration of ivabradine in blood plasma increases the risk of severe bradycardia.

Contraindicated combinations

Concomitant use with strong cytochrome P450 inhibitors, such as azole antifungal agents (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, ketoconazole (at a dose of 200 mg 1 time per day) or josamycin (at a dose of 1 g 2 times a day), increases the average concentration of ivabradine in blood plasma by 7-8 times.

Not recommended combinations

Moderate-acting CYP3A4 inhibitors. The combined use of ivabradine and heart rate-reducing agents-diltiazem or verapamil, was well tolerated by patients and was accompanied by an increase in the concentration of ivabradine by 2-3 times, with an additional decrease in heart rate of approximately 5 beats / min.

This combination is not recommended.

Combinations that require caution when using

Moderate-acting CYP3A4 inhibitors. Concomitant use of ivabradine with other CYP3A4 inhibitors (for example, fluconazole) should begin with an initial dose of 2.5 mg 2 times a day. If the heart rate is less than 60 beats / min, careful monitoring of the heart rate is necessary.

Grapefruit juice. While taking grapefruit juice, there was a 2-fold increase in the concentration of ivabradine in the blood. During ivabradine therapy, grapefruit juice intake should be kept to a minimum.

CYP3A4 inducers, such as rifampicin, barbiturates, phenytoin, and herbal preparations containing St. John’s wort (Hypericum perforatum), when used together, can lead to a decrease in the blood concentration and activity of ivabradine and require a higher dose of ivabradine. During ivabradine therapy, the use of drugs and products containing St. John’s wort should be kept to a minimum.

Combined use with other medicinal products

There was no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine in the following drugs: proton pump inhibitors (omeprazole, lansoprazole), phosphodiesterase-5 inhibitors (sildenafil), HMG-CoA reductase inhibitors (simvastatin), BCC derivatives of the dihydropyridine series (amlodipine, lacidipine), digoxin, etc. warfarin.

Ivabradine was shown to have no clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, the pharmacokinetics and pharmacodynamics of digoxin, warfarin, and the pharmacodynamics of acetylsalicylic acid.

In the Phase III pilot study, the use of the following drugs had no special restrictions, and therefore they can be prescribed in combination with ivabradine without special precautions: ACE inhibitors, angiotensin II receptor antagonists, diuretics, short-and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral hypoglycemic agents, acetylsalicylic acid and other antithrombotic agents.

How to take, course of use and dosage

Coraxan should be taken orally 2 times a day, in the morning and in the evening with meals.

Stable angina pectoris. The recommended initial dose of the drug is 10 mg per day (1 tablet of 5 mg 2 times a day). Depending on the therapeutic effect, after 3-4 weeks of use, the daily dose of the drug can be increased to 15 mg (1 tablet of 7.5 mg 2 times a day). If during therapy with Coraxan, the resting heart rate is reduced to less than 50 beats / min, or the patient has symptoms associated with bradycardia (such as dizziness, fatigue, or a pronounced decrease in blood pressure), it is necessary to reduce the dose of Coraxan (for example, to 2.5 mg (1/2 tablet of 5 mg) 2 times a day). If the dose of Coraxan is reduced to less than 50 beats/min, or if symptoms of severe bradycardia persist, then the drug should be discontinued.

Chronic heart failure. The recommended initial dose of Coraxan is 10 mg per day (1 tablet of 5 mg 2 times a day). After two weeks of use, the daily dose of Coraxan can be increased to 15 mg (1 tablet 7.5 mg 2 times a day), if the resting heart rate is stable more than 60 beats / min. If the heart rate is stable no more than 50 beats / min or in case of symptoms of bradycardia, such as dizziness, fatigue or hypotension, the dose can be reduced to 2.5 mg (1/2 tablet 5 mg) 2 times a day. If the heart rate is in the range of 50 to 60 beats / min, it is recommended to use the drug Coraxan at a dose of 5 mg 2 times a day. If the resting heart rate is consistently less than 50 beats/min during the course of using the drug, or if the patient has symptoms of bradycardia, the dose of the drug should be reduced for patients receiving Coraxan at a dose of 5 mg 2 times a day or 7.5 mg 2 times a day. If patients receiving Coraxan at a dose of 2.5 mg (1/2 tablet 5 mg) 2 times a day or 5 mg 2 times a day have a stable resting heart rate of more than 60 beats / min, the dose of the drug may be increased. If the heart rate does not exceed 50 beats/min or the patient still has symptoms of bradycardia, the drug should be discontinued.

For patients aged 75 years and older, the recommended initial dose of Coraxan is 2.5 mg (1/2 tablet of 5 mg) 2 times a day. In the future, it is possible to increase the dose of the drug.

Impaired renal function. In patients with creatinine clearance greater than 15 ml / min, the recommended initial dose of Coraxan is 10 mg per day (1 tablet of 5 mg 2 times a day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tablet of 7.5 mg 2 times a day). Due to the lack of clinical data on the use of Coraxan in patients with creatinine clearance less than 15 ml/min, the drug should be used with caution.

Impaired liver function. In patients with mild hepatic insufficiency (up to 7 points on the Child – Pugh scale), the usual dosage regimen is recommended. The recommended initial dose of Coraxan is 10 mg per day (1 tablet of 5 mg 2 times a day). Depending on the therapeutic effect, after 3-4 weeks of use, the dose of the drug can be increased to 15 mg (1 tablet of 7.5 mg 2 times a day).

Overdose

Symptoms:  severe and prolonged bradycardia.

Treatment of severe bradycardia should be symptomatic and carried out in specialized departments. If bradycardia develops in combination with impaired hemodynamic parameters, symptomatic treatment with intravenous use of beta-adrenomimetics, such as isoprenaline, is indicated.

If necessary, an artificial pacemaker can be installed.

Special instructions

Cardiac Arrhythmiacoraxan is ineffective for the treatment or prevention of arrhythmias. Its effectiveness decreases with the development of tachyarrhythmias (for example, ventricular or supraventricular tachycardia). The drug is not recommended for patients with atrial fibrillation (atrial fibrillation). or other types of arrhythmias related to sinus node function. During therapy, patients should be clinically monitored for atrial fibrillation (paroxysmal or persistent). In case of clinical indications (for example, worsening of angina pectoris, palpitation, irregular heart rate), an ECG should be included in the current monitoring.

Use in patients with bradycardia Coraxan is contraindicated if the resting heart rate is less than 60 beats / min before starting therapy. If the patient’s resting heart rate is reduced to less than 50 beats/min during therapy, or if the patient has symptoms associated with bradycardia (such as dizziness, fatigue, or hypotension), it is necessary to reduce the dose of the drug. If the heart rate is reduced to less than 50 beats/min, or symptoms associated with bradycardia persist, then Coraxan should be discontinued.

Combined use as part of anti-anginal therapy, the use of Coraxan in combination with BMCC that reduce heart rate, such as verapamil or diltiazem, is not recommended. When ivabradine was used in combination with nitrates and dihydropyridine derivatives such as amlodipine, no changes in the safety profile of the therapy were observed. Combined use with BMCC has not been shown to increase the efficacy of ivabradine.

It is not recommended to prescribe the drug immediately after a stroke, because there are no data on the use of the drug during this period.

Visual perception Functioncoraxan affects the function of the retina of the eye. Currently, no toxic effects of ivabradine on the retina have been identified, but the effect of the drug on the retina with prolonged use (over 1 year) is currently unknown. If visual impairments occur that are not described in these instructions, discontinuation of Coraxan ® should be considered. Patients with retinal pigmentation degeneration (retinitis pigmentosa) should take Coraxan with caution.

Excipients The drug contains lactose, so Coraxan is not recommended for patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.

Arterial hypotension Due to insufficient clinical data, the drug should be administered with caution in patients with arterial hypotension. Coraxan is contraindicated in patients with severe hypotension (systolic blood pressure less than 90 mm Hg and diastolic blood pressure less than 50 mm Hg).

Atrial fibrillation (atrial fibrillation) – cardiac arrhythmias An increased risk of severe bradycardia has been shown with Coraxan when sinus rhythm is restored during pharmacological cardioversion. However, due to the lack of sufficient data, if it is possible to delay electrical cardioversion, Coraxan should be discontinued 24 hours before it is performed.

Use in patients with congenital long QT syndrome or patients taking drugs that prolong the QT interval Coraxan should not be prescribed in patients with congenital long QT syndrome, or in combination with drugs that prolong the QT interval. If such therapy is necessary, strict ECG monitoring is necessary.

Moderate hepatic insufficiencyin case of moderate hepatic insufficiency (less than 9 points on the Child-Pugh scale), therapy with Coraxan should be carried out with caution.

Severe renal insufficiency In severe renal insufficiency (creatinine clearance less than 15 ml/min), therapy with Coraxan should be carried out with caution.

Form of production

Film-coated tablets.

Storage conditions

No special storage conditions are required

Shelf life

3 years

Active ingredient

Ivabradin

Conditions of release from pharmacies

By prescription

Dosage form

Tablets