Coraxan film-coated pills 7.5mg N56
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Active ingredients
Ivabradin
Release form
Pills
Composition
Active ingredient: Ivabradine hydrochloride Concentration of active ingredient (mg): 8.085
Pharmacological effect
PharmacokineticsIvabradine is a S-enantiomer with no bioconversion according to in vivo studies. The main active metabolite of the drug is an N-desmethylated derivative of ivabradine. Absorption and bioavailability Ivabradine is rapidly and almost completely absorbed in the gastrointestinal tract after oral administration. Cmax in plasma is reached approximately 1 hour after ingestion on an empty stomach. Bioavailability is approximately 40%, due to the effect of the first passage through the liver. Eating increases the absorption time by approximately 1 hour and increases plasma concentration from 20% to 30%. To reduce the variability of the concentration of the drug is recommended to be taken simultaneously with a meal (see section Dosing regimen). Distribution Binding to plasma proteins is approximately 70%. Vd in equilibrium - about 100 liters. Cmax in plasma after prolonged use at the recommended dose of 5 mg 2 times / day is approximately 22 ng / ml (coefficient of variation = 29%). The mean plasma Css is 10 ng / ml (coefficient of variation = 38%). Metabolism Ivabradine is largely metabolized in the liver and intestines by oxidation, involving only the CYP3A4 isoenzyme. The main active metabolite is the N-desmethylated derivative (S 18982), which accounts for 40% of the dose of ivabradine concentration. Metabolism of the active metabolite of ivabradine also occurs in the presence of the CYP3A4 isoenzyme. Ivabradine has a low affinity for the CYP3A4 isoenzyme, does not induce or inhibit it. In this regard, it is unlikely that ivabradine influences the metabolism or concentration of substrates of CYP3A4 isoenzyme in the blood plasma. On the other hand, the simultaneous use of potent inhibitors or inducers of cytochrome P450 can significantly affect the concentration of ivabradine in the blood plasma (see sections Drug Interactions and Specific Instructions). Output T1 / 2 ivabradine is, on average, 2 hours (70-75% AUC) , effective T1 / 2 - 11 h. Total clearance - about 400 ml / min, renal - about 70 ml / min. Excretion of metabolites occurs at the same rate through the kidneys and intestines.About 4% of the dose taken is excreted by the kidneys unchanged. Linearity and non-linearity The pharmacokinetics of ivabradine are linear in the dose range from 0.5 to 24 mg. Specific patient groups Elderly and senile patients. Pharmacokinetic parameters (AUC and Cmax) do not significantly differ in the groups of patients 65 years and older, 75 years and older, and the general population of patients (see section Dosage regimen). Renal dysfunction. The effect of renal failure (CC from 15 to 60 ml / min) on the kinetics of ivabradine is minimal, since only about 20% of ivabradine and its active metabolite S 18982 are excreted by the kidneys (see section Dosage regimen). Liver dysfunction. In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale), the AUC of free ivabradine and its active metabolite is 20% higher than in patients with normal liver function. Data on the use of ivabradine in patients with moderate (7–9 points on the Child-Pugh scale) liver failure is limited and does not allow us to conclude about the features of the pharmacokinetics of the drug in this group of patients. Data on the use of ivabradine in patients with severe (more than 9 points on the Child-Pugh scale) liver failure is currently not available (see section Dosage regimen). The relationship between pharmacokinetic and pharmacodynamic properties Analysis of the relationship between pharmacokinetic and pharmacodynamic properties made it possible to establish that the decrease in heart rate is in direct proportion to the increase in the concentration of ivabradine and the active metabolite S 18982 in the blood plasma when taken in doses up to 15-20 mg 2 times / day. At higher doses of the drug, the slowing of the heart rate does not have a proportional dependence on the concentration of ivabradine in the blood plasma and is characterized by a tendency to reach a plateau. High concentrations of ivabradine, which can be achieved with a combination of the drug with powerful inhibitors of the CYP3A4 isoenzyme, can lead to a pronounced decrease in heart rate, but this risk is lower when combined with moderate inhibitors of the CYP3A4 isoenzyme (see Contraindications, Drug Interactions, and Special Instructions).
Indications
Ivabradine is a drug that slows the rhythm of the heart, the mechanism of action of which is the selective and specific inhibition of If channels of the sinus node, controlling spontaneous diastolic depolarization in the sinus node and regulating heart rate.atrioventricular and intraventricular pathways, as well as myocardial contractility and ventricular repolarization. Ivabradin can also interact with Ih retinal channels, similar to If, heart channels that are involved in the occurrence of a temporary change in the visual perception system by changing the response of the retina to bright light stimuli. Under provoking circumstances (for example, a quick change of brightness in the field of the visual field), partial inhibition of Ih channels by ivabradine causes changes photoreception (photopsia). The photopsy is characterized by a transient change in brightness in a limited area of the visual field (see the Adverse Effect section). The main pharmacological feature of Ivabradine is its ability to dose-dependent decrease in heart rate. Analysis of the dependence of the HR reduction on the dose of the drug was carried out with a gradual increase in the dose of ivabradine to 20 mg 2 times / day and revealed a tendency to achieve a plateau effect (no increase in the therapeutic effect with a further increase in dose), which reduces the risk of severe bradycardia (HR less than 40 beats ./min) (see section Side Effects). When prescribing a drug at recommended doses, the degree of reduction in heart rate depends on its initial value and is approximately 10-15 beats per minute at rest and during exercise. As a result, the cardiac function decreases and myocardial oxygen demand decreases. Ivabradine does not affect intracardiac conductivity, myocardial contractility (does not cause a negative inotropic effect) or the process of ventricular repolarization of the heart. In clinical electrophysiological studies, ivabradine did not affect the duration of the impulses along the atrioventricular or intraventricular pathways, as well as the corrected QT intervals. In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF), 30-45%) It was shown that ivabradine does not affect the contractility of the myocardium. It was established that ivabradine at a dose of 5 mg 2 times / day improved the performance of stress tests after 3-4 weeks of therapy. Efficacy was confirmed for a dose of 7.5 mg 2 times / day.In particular, an additional effect with increasing doses from 5 mg to 7.5 mg 2 times / day was established in a comparative study with atenolol. The exercise time increased by about 1 minute after 1 month of using ivabradine at a dose of 5 mg 2 times / day, while after an additional 3-month course of taking ivabradine at a dose of 7.5 mg, 2 times / day, a further increase of this indicator was noted by 25 seconds Anti-anginal and anti-ischemic activity of ivabradine was confirmed for patients aged 65 years and older. Ivabradine efficacy when used in doses of 5 mg and 7.5 mg 2 times / day was observed in relation to all indicators of stress tests (total duration of exercise, the time until a limiting attack of angina, the time before the start of an attack of angina and 1 mm of ST) , and was also accompanied by a decrease in the incidence of angina attacks by about 70%. The use of ivabradine 2 times / day provided constant therapeutic efficacy for 24 hours. In patients taking ivabradine, the additional efficacy of ivabradine was shown in relation to all indicators of stress tests, when atenolol (50 mg) was added to the maximum dose during the decline of therapeutic activity (12 hours after ingestion). Improved efficacy of ivabradine is not shown when amlodipine is added to the maximum dose of therapeutic activity (12 hours after ingestion), while At the maximum of activity (3-4 hours after ingestion), the additional efficacy of ivabradine was proven. In studies of the clinical efficacy of the drug, the effects of ivabradine were fully preserved during the 3- and 4-month periods of treatment. During treatment, signs of development of tolerance (loss of effectiveness) were absent, and after discontinuation of treatment, the withdrawal syndrome was not observed. The anti-anginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as a significant decrease in the work of work (heart rate × systolic blood pressure), both at rest and during exercise. The effect on BP and OPSI was insignificant and clinically insignificant. A steady decrease in heart rate was observed in patients taking ivabradine for at least 1 year.The effects on carbohydrate metabolism and lipid profile were not observed. In patients with diabetes, the efficacy and safety of ivabradine were similar to those in the general population of patients. In a study in patients with IHD without clinical manifestations of heart failure (LVEF over 40%) against the background maintenance therapy, therapy with ivabradine in doses higher than recommended (initial dose of 7.5 mg 2 times / day (5 mg 2 times / day, at the age of 75 years old), which was then titrated to 10 mg 2 times / day) did not have a significant effect on and the primary combined endpoint (death due to a cardiovascular cause or the development of non-fatal myocardial infarction). The incidence of bradycardia in the group of patients receiving ivabradine was 17.9%. 7.1% of patients in the study took verapamil, diltiazem, or potent inhibitors of the CYP3A4 isoenzyme. Patients with angina class II or higher, according to the classification of the Canadian Cardiological Society, showed a small statistically significant increase in the incidence of primary combination endpoint with ivabradine — which was not observed a subgroup of all patients with angina pectoris (class I and above). In a study involving patients with stable angina pectoris and left ventricular dysfunction (F VLS is less than 40%), 86.9% of which received beta-blockers, did not reveal differences between groups of patients taking ivabradine against the background of standard therapy, and placebo, in terms of the total frequency of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization about the occurrence of new cases of heart failure or an increase in the symptoms of chronic heart failure (CHF). In patients with symptomatic angina, there were no significant differences in the incidence of death due to cardiovascular causes or hospitalization due to the development of nonfatal myocardial infarction or heart failure (incidence 12.0% in the ivabradine group and 15.5% in the placebo group, respectively). The use of ivabradine in patients with a heart rate of at least 70 beats per minute shows a decrease in the frequency of hospitalizations for fatal and nonfatal myocardial infarction by 36% and the frequency of revascularization by 30%. Patients with exertional angina pectoris against the background of receiving ivabradine showed a decrease in the relative risk of onset complications (death rate from cardiovascular diseases,hospitalization for acute myocardial infarction, hospitalization for the occurrence of new cases of heart failure or worsening symptoms of CHF) by 24%. The noted therapeutic advantage is achieved, first of all, by reducing the frequency of hospitalization for acute myocardial infarction by 42%. Reducing the frequency of hospitalization for fatal and nonfatal myocardial infarction in patients with heart rate more than 70 beats / min is even more significant and reaches 73% . On the whole, the good tolerability and safety of the drug were noted. Against the background of ivabradine use in patients with CHF II-IV FC, according to the NYHA classification with LVEF less than 35%, a clinically and statistically significant decrease in the relative risk of complications (cardiovascular deaths and the number of hospitalizations due to increased symptoms of CHF) by 18%. The absolute risk reduction was 4.2%. A pronounced therapeutic effect was observed after 3 months from the start of therapy. Reducing mortality from cardiovascular diseases and reducing the number of hospitalizations due to increased symptoms of CHF was observed regardless of age, sex, functional class of CHF, use of beta-blockers, ischemic or non-ischemic etiology of CHF , the presence of diabetes mellitus or arterial hypertension in history. Patients with symptoms of CHF with sinus rhythm and heart rate of at least 70 beats / min received standard therapy, including beta-adrenergic blockers (89%), 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 the use of ivabradine, improvement in the functional class of CHF according to the NYHA classification is shown. Patients with a heart rate of 80 beats / min have a decrease in heart rate by an average of 15 beats / min.
Contraindications
Coraxan should be taken orally 2 times a day, morning and evening during the meal. Stable angina. The recommended initial dose of the drug is 10 mg per day (1 tablet 5 mg 2 times a day).Depending on the therapeutic effect, after 3-4 weeks of application, 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 heart rate is reduced to less than 50 beats / min, or the patient has symptoms associated with bradycardia (such as dizziness, increased 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 5 mg) 2 times a day). If at lower doses of the drug Coraxan heart rate remains less than 50 beats. / min, or symptoms of severe bradycardia persist, then the drug should be stopped. 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 of 7.5 mg 2 times a day) if the heart rate at rest is stable over 60 beats. / min If the heart rate is stable no more than 50 beats. / min or in the 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 value of the heart rate is in the range from 50 to 60 beats. / min, it is recommended to use the drug Coraxan at a dose of 5 mg 2 times a day. If during the use of the drug, the heart rate at rest is consistently less than 50 beats. / min, or if the patient has symptoms of bradycardia, for patients receiving Coraxan 5 mg twice a day or 7.5 mg twice a day, the dose should be reduced. If patients receiving the drug Coraxan at a dose of 2.5 mg (1/2 tablet 5 mg) 2 times a day or 5 mg 2 times a day, the heart rate at rest is stable over 60 beats. / min, the dose of the drug may be increased. If the heart rate is not more than 50 beats. / min or the patient has bradycardia symptoms, the use of 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 5 mg) 2 times a day. In the future, may increase the dose of the drug. Impaired renal function. For patients with QA more than 15 ml / min, the recommended initial dose of Coraxan is 10 mg per day (1 tablet 5 mg 2 times per 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 7.5 mg 2 times a day).Due to the lack of clinical data on the use of the drug Coraxan in patients with QA less than 15 ml / min, the drug should be used with caution. Liver dysfunction. Patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale) are recommended to use the usual dosage regimen. 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 7.5 mg 2 times a day).
Precautionary measures
Hypersensitivity to ivabradine or any of the coraxan excipients; Bradycardia (heart rate at rest less than 60 beats / min (before treatment)); cardiogenic shock; acute myocardial infarction; severe hypotension (systolic blood pressure less than 90 mm Hg. Art. and diastolic blood pressure less than 50 mm Hg. Art.); severe liver failure (more than 9 points on the Child-Pugh scale); sick sinus syndrome; sinoatrial blockade; the presence of an artificial pacemaker; unstable angina; atrioventricular (AV) blockade of the III degree; simultaneous use with potent inhibitors of cytochrome P450 3A4 system isoenzymes, such as antifungal agents of the azoles group (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin for oral administration, josamycin, telithromycin), HIV protease inhibitors (cephalonistine, imitine, etc.), antiviral therapy, antiviral therapy, antiviral therapy, antiviral therapy; pregnancy and lactation period; age up to 18 years (efficacy and safety of the drug in this age group has not been studied); lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome.
Use during pregnancy and lactation
The lack of a positive effect on clinical outcomes in patients with symptomatic stable angina Ivabradine is indicated only as a symptomatic treatment of stable angina, as ivabradine does not have a positive effect on the incidence of cardiovascular events (for example, myocardial infarction or death due to cardiovascular causes) in patients with symptomatic angina pectoris. Heart rate monitoring Considering the significant variability of heart rate during the day, before starting therapy and when taking Coraxan or when deciding to titrate a dose, the determination of heart rate should be performed in one of the following ways: serial measurement of heart rate, ECG, or 24-hour outpatient monitoring.Such a determination should also be made to patients with low heart rate, in particular, if the heart rate drops below 50 beats / min, or when the dose of Coraxan is lowered (see section Dosage regimen). Heart rhythm disordersCoraxan is not effective for treating or preventing arrhythmias. Its effectiveness decreases with the development of tachyarrhythmias (for example, ventricular or supraventricular tachycardia). Coraxan is not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function. Patients taking ivabradine have an increased risk of developing atrial fibrillation (see the Adverse Effects section). Atrial fibrillation was more common among patients who were taking amiodarone or class I antiarrhythmic drugs simultaneously with ivabradine. During therapy with Coraxan, clinical monitoring of patients for atrial fibrillation should be performed (paroxysmal or permanent). In case of clinical indications (for example, worsening of the course of stenocardia, appearance of a sensation of heartbeat, irregular heart rhythm), an ECG should be included in the current control. Patients should be informed about the signs and symptoms of atrial fibrillation and should be advised to consult a doctor if symptoms occur. If atrial fibrillation occurs during therapy, the ratio of the expected benefit to the possible risk with the further use of Ivabradine should be carefully reviewed again. Patients with chronic heart failure and intraventricular conduction disorders (blockade of the left or right bundle of His) and ventricular dissynchrony should be closely monitored control. Use of coraxane in patients with bradycardia is contraindicated if, before initiating therapy, the heart rate at rest is less than 70 beats / min (see Affairs Contraindications). 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), reduce the dose of Coraxan. If, at lower doses of the drug, the heart rate remains below 50 beats / min, or symptoms associated with bradycardia persist, then taking Coraxan should be stopped (seesection Dosage regimen). Combined use as part of antianginal therapy. The use of Coraxan in conjunction with slow calcium channel blockers that reduce heart rate, such as verapamil or diltiazem, is contraindicated (see Contraindications and Drug Interactions). With the combined use of ivabradine with nitrates and blockers of slow calcium channels - derivatives of the dihydropyridine series, such as amlodipine, there was no change in the safety profile of the therapy being administered. It has not been established that simultaneous use with slow calcium channel blockers increases the effectiveness of ivabradine (see Pharmacological Action section). Chronic heart failure The question of administering Coraxan should be considered only in patients with stable heart failure. Coraxan should be used with caution in patients with chronic heart failure IV FC according to the NYHA classification, due to limited application data for this group of patients. It is not recommended to prescribe Coraxan immediately after a stroke, because There are no data on the use of the drug in this period. The functions of visual perceptionCoraxan affects the function of the retina (see Pharmacological action section). To date, no toxic effect of ivabradine on the retina has been identified, however, the effect of the drug on the retina with prolonged use (over 1 year) is unknown today. If unexpected disturbances of visual functions occur, it is necessary to consider discontinuing Coraxan. Patients with retinal pigment degeneration (retinitis pigmentosa) should take Coraxan with caution (see the section With caution). Auxiliary substances The drug contains lactose, therefore Coraxan is not recommended for patients with lactase deficiency, lactose intolerance, glucose-galactose maloperast syndrome. - for an insufficient amount of clinical data, Coraxan should be prescribed with caution in patients with mild and moderate arterial hypotension. Coraxan is against kettle with severe arterial hypotension (systolic blood pressure less than 90 mmHgand diastolic blood pressure less than 50 mm Hg) (see section Contraindications). Atrial fibrillation (atrial fibrillation) - cardiac arrhythmias There is no evidence of an increased risk of developing severe bradycardia while taking Coraxan while restoring sinus rhythm during pharmacological cardioversion. However, due to the lack of sufficient data, if possible, to delay planned electrical cardioversion, taking Coraxan should be discontinued 24 hours prior to its implementation. Use in patients with congenital long QT interval syndrome or patients taking drugs extending the QT interval should be prescribed for congenital long QT syndrome, as well as in combination with drugs that extend the QT interval (see the Drug Interactions section). If necessary, such therapy requires strict ECG monitoring (see section Special Instructions). Reducing heart rate, incl. due to coraxan, may exacerbate the prolongation of the QT interval, which, in turn, may trigger the development of a severe form of arrhythmia, in particular, polymorphic ventricular tachycardia such as pirouette. Patients with arterial hypertension who need to change antihypertensive therapy in the group of patients taking Coraxan (7.1%) compared with the placebo group (6.1%). These cases occurred particularly often soon after a change in antihypertensive therapy; they were temporary and did not affect the efficacy of Coraxan. When changing antihypertensive therapy in patients with chronic heart failure, taking Coraxan, monitoring of blood pressure is required at appropriate intervals (see section Side Effects). Moderate hepatic failureWhen moderate hepatic insufficiency (less than 9 points on the Child-Pugh scale), Coraxan therapy should carry out with caution (see section Dosage regimen). Severe renal failureWhen severe renal insufficiency (CC is less than 15 ml / min), Corax therapy An should be done with caution.
Dosage and administration
Stable angina Therapy of stable angina in patients with normal sinus rhythm: - with intolerance or the presence of contraindications to the usebeta-blockers in combination with beta-blockers with inadequate control of stable angina on the background of the optimal dose of beta-blocker Chronic heart failure To reduce the incidence of cardiovascular complications (mortality from cardiovascular diseases and hospitalization due to increased symptoms of heart failure) in patients chronic heart failure, with sinus rhythm and heart rate of at least 70 beats. / min
Side effects
The patient should inform the doctor about all the drugs taken. Unwanted drug combinations Medicines that prolong 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). Simultaneous use of ivabradine should be avoided. a and these drugs, because the decrease in heart rate can cause additional lengthening of the QT interval. If necessary, the joint appointment of these drugs should be carefully monitored ECG indicators (see section Special instructions). Concomitant use with caution It is necessary to use Coraxan with potassium-sparing diuretics with caution (diuretics of the thiazide group and loop diuretics), because 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 QT lengthening syndrome, both congenital and caused by exposure to any substances. liver with the participation of cytochrome P450 isoenzymes (CYP3A4 isoenzyme) and is a very weak inhibitor of this cytochrome. Ivabradine does not have a 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 has been found that CYP3A4 isoenzyme inhibitors increase, and CYP3A4 isoenzyme inducers reduce plasma concentrations of ivabradine. Increasing plasma concentrations of ivabradine may increase the risk of developing bradycardia (see the section on Special Instructions). such as antifungals of the azoles group (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin for Oral administration, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, are contraindicated (see Contraindications). Potent inhibitors of CYP3A4 isoenzyme - ketoconazole (200 mg 1 time / day) or josamycin (1 g 2 times / day) increase average plasma concentrations of ivabradine 7-8 times. Simultaneous use of ivabradine and moderate inhibitors of CYP3A4 isoenzyme diltiazem or verapamil ( means of reducing 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 reduction in heart rate by 5 beats / min. This application is contraindicated (see section Contraindications). Unwanted combinations of drugsIn a background of taking grapefruit juice, there was a 2-fold increase in the exposure of Ivabradine. During the period of therapy with Coraxan, grapefruit juice should be avoided whenever possible. Drug combinations requiring caution Use of ivabradine in combination with other moderate CYP3A4 isoenzyme inhibitors (for example, fluconazole) is possible provided that the heart rate at rest is more than 70 beats / min. The recommended initial dose of ivabradine is 2.5 mg 2 times / day. Control of heart rate is necessary. CYP3A4 isoenzyme inducers, such as rifampicin, barbiturates, phenytoin, and herbal remedies containing St. John's wort, when used together, can lead to a decrease in blood 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 therapy with Coraxan, use of drugs and products should be avoided whenever possible.containing St. John’s wort for example, simvastatin), slow calcium channel blockers - derivatives of the dihydropyridine series (for example, amlodipine, lacidipine), digoxin and warf Arina. 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 was used in combination with ACE inhibitors, the antagonist