Coraxan, 5 mg 56 pcs

Ivabradine is a heart rhythm slowing drug whose mechanism of action consists in selective and specific inhibition of I_f sinus node channels that control spontaneous diastolic depolarization in the sinus node and regulate heart rate (HR). Ivabradine has a selective effect on the sinus node without affecting the timing of impulse conduction along the intraatrial, atrial-ventricular and intraventricular conduction pathways, as well as on myocardial contractility and ventricular repolarization.

Ivabradine may also interact with the I_h channels of the retina, similar to the I_f channels of the heart, involved in causing temporary changes in the visual perception system by changing the retinal response to bright light stimuli.

In provocative circumstances (e.g., a rapid change in brightness in the visual field), partial inhibition of the I_h channels by ivabradine causes the phenomenon of changes in light perception (photopsia). Photopsia is characterized by a transient change in brightness in a limited area of the visual field (see section “Side effects”). The main pharmacological feature of ivabradine is the ability of dose-dependent reduction of heart rate (HR). Analysis of dose-related HR slows-down was performed with gradual increase of iwabradine dose up to 20 mg twice daily and showed the tendency to reach the “plateau” effect (no increase of therapeutic effect with further dose increase), which reduces the risk of bradycardia (HR under 40 bpm) (see section “Side effect”).

When administering the drug in the recommended doses, the degree of HR reduction depends on its initial value and is about 10-15 beats/min at rest and during physical activity. As a result, heart work decreases and myocardial oxygen demand decreases.

Ivabradine has no effect on intracardiac conduction, myocardial contractility (does not cause negative inotropic effect) and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine had no effect on the pulse conduction time along the atrial-ventricular or intraventricular conduction pathways, as well as on the corrected QT intervals. In studies involving patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%) it has been shown that ivabradine has no effect on myocardial contractility.

Ivabradine in a dose of 5 mg twice daily was found to improve exercise test values after 3-4 weeks of therapy. The efficacy was also confirmed for the dose of 7.5 mg 2 times daily. In particular, an additional effect of increasing the dose from 5 to 7.5 mg 2 times a day was established in a comparative study with atenolol. Exercise time increased by about 1 minute after 1 month of using ivabradine at a dose of 5 mg 2 times a day, and after an additional 3-month course of taking ivabradine at a dose of 7.5 mg 2 times a day orally, a further increase of 25 seconds in this parameter was noted. Antianginal and anti-ischemic activity of ivabradine was also confirmed for patients aged 65 years and older. The efficacy of ivabradine when used in doses of 5 mg and 7.5 mg 2 times daily was observed for all exercise test parameters (total exercise duration, time to limiting angina attack, time to onset of angina attack and time to ST-segment depression by 1 mm) and was accompanied by approximately 70% reduction of angina attack frequency. Administration of ivabradine 2 times a day provided continuous therapeutic efficacy for 24 hours.

In patients taking ivabradine additional efficacy of ivabradine in all exercise test parameters was shown when added to the maximum dose of atenolol (50 mg) at the therapeutic decline (12 hours after oral administration).
No improvement in the efficacy of ivabradine has been shown when added to the maximum dose of amlodipine at the onset of therapeutic activity (12 hours after oral administration), whereas at the peak of activity (3 to 4 hours after oral administration) additional efficacy of ivabradine has been demonstrated.

In clinical efficacy studies, the effects of ivabradine were fully sustained over 3 and 4 month treatment periods. There were no signs of tolerance (decrease in efficacy) during treatment, and no “withdrawal” syndrome was observed after discontinuation of treatment. Antianginal and anti-ischemic effects of ivabradine were associated with dose-dependent reduction of HR, as well as with a significant reduction of the work product (HR × systolic blood pressure), both at rest and during physical activity. The effects on blood pressure (BP) and total peripheral vascular resistance (TPR) were insignificant and clinically insignificant.

Sustained HR slowing was noted 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 of ivabradine were similar to those in the general patient population.

. No differences were found between the groups of patients who received ivabradine against standard therapy and patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-adrenoblockers, and placebo, in the cumulative incidence of cardiovascular deaths, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or increased symptoms of chronic heart failure (CHF), and in a subgroup of patients with a HR of at least 70 bpm./min.

The use of ivabradine in patients with HR of 70 bpm or higher was shown to decrease the rate of hospitalizations for fatal and non-fatal myocardial infarction by 36% and the rate of revascularization by 30%.

In patients with angina pectoris on ivabradine 24 % decrease of relative risk of complications (rate of cardiovascular deaths, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or increase of CHF symptoms) was noted. The noted therapeutic benefit is achieved primarily due to a 42% reduction in the rate of hospitalization for acute myocardial infarction.
Reduction of hospitalization rate for fatal and non-fatal myocardial infarction in patients with HR over 70 bpm is even more significant and reaches 73 %. In general, good tolerability and safety of the drug were noted.

In iwabradine use in patients with CHF of II-IV functional class according to NYHA classification with LVEF less than 35 % showed clinically and statistically significant 18 % decrease of relative risk of complications (incidence of cardiovascular deaths and decrease of hospitalization rate due to elevated symptoms of CHF). The absolute risk reduction was 4.2%. Expressed therapeutic effect was observed after 3 months from the therapy start.

The decrease of cardiovascular mortality and decrease of hospitalizations due to the worsening of CHF symptoms was observed regardless of age, sex, functional class of CHF, beta-adrenoblockers use, ischemic or non-ischemic etiology of CHF, presence of diabetes mellitus or hypertension in anamnesis.

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

The use of ivabradine for 1 year has been shown to prevent one death or one hospitalization due to cardiovascular disease for every 26 patients taking the drug. Improvement of functional class of coronary artery disease according to NYHA classification was shown during use of ivabradine.

In patients with an HR of 80 bpm there was an average decrease in HR of 15 bpm.

Pharmacokinetics

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 administration. Maximum concentration (C_max ) in blood plasma is reached approximately 1 hour after oral administration on an empty stomach. Bioavailability is approximately 40%, which is due to the effect of “first passage” through the liver.

Eating increases absorption time by about 1 hour and increases plasma concentration from 20% to 30%. In order to reduce the variability of concentrations the drug is recommended to be taken simultaneously with meals (see section “Dosage and administration”).

Distribution

The binding to plasma proteins is approximately 70%. The volume of distribution in the equilibrium state is about 100 l. Cmax in plasma after long-term use at the recommended dose of 5 mg twice daily is approximately 22 ng/ml (coefficient of variation = 29 %). Mean equilibrium plasma concentration is 10 ng/ml (coefficient of variation=38%).

The metabolism of Ivabradine is largely metabolized in the liver and intestine by oxidation involving only cytochrome P450 3A4 (CYP3A4 isoenzyme). The main active metabolite is N-desmethylated derivative (S 18982), which accounts for 40% of the dose concentration of ivabradine. Metabolism of the active metabolite of ivabradine also occurs in the presence of CYP3A4 isoenzyme. Ivabradine has low affinity to CYP3A4 isoenzyme and does not induce or inhibit it. Therefore, it is unlikely that ivabradine affects the metabolism or plasma concentrations of CYP3A4 isoenzyme substrates. On the other hand, concomitant use of potent cytochrome P450 inhibitors or inducers may significantly affect the plasma concentration of ivabradine (see sections “Interaction with other medicinal products” and “Cautions”).

Elimination

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)), effective T_1/2 is 11 hours. Total clearance is approximately 400 ml/min, renal clearance approximately 70 ml/min. Metabolites are excreted at the same rate through the kidneys and intestines. About 4% of the taken dose is excreted unchanged by the kidneys.

Linearity and nonlinearity

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

Indications

Stable angina
The therapy of stable angina in patients with normal sinus rhythm:
– In intolerance or contraindications to the use of beta-adrenoblockers
– In combination with beta-adrenoblockers in inadequate control of stable angina pectoris against optimal dose of beta-adrenoblocker

Chronic heart failure

To reduce the incidence of cardiovascular complications (cardiovascular mortality and hospitalization due to worsening symptoms of CHF) in patients with chronic heart failure, with sinus rhythm and HR of at least 70 bpm./min.

Active ingredient

Composition

1 tablet of 5 mg contains:

The active ingredient:

ivabradine hydrochloride 5.39 mg, corresponding to 5.0 mg of base.

Auxiliary substances:

Lactose monohydrate 63.91 mg,

Magnesium stearate 0.5 mg,

corn starch 20 mg,

maltodextrin 10 mg,

colloidal anhydrous silica 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.

How to take, the dosage

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

Stable angina pectoris. Recommended initial dose of the preparation is 10 mg per day (1 tablet of 5 mg two times per day).
Depending on the therapeutic effect, after 3-4 weeks of using the drug the daily dose can be increased up to 15 mg (1 tablet of 7.5 mg two times per day). If during the treatment by Coraxan HR at rest falls below 50 BPM, or if the patient experiences bradycardia-related symptoms (such as dizziness, increased fatigability or marked BP decrease), it is necessary to decrease Coraxan dosage (for example, to 2.5 mg (1/2 5 mg tablet) 2 times per day). If on decreasing the dose of Coraxan the HR is still less than 50 bpm, or there are still symptoms of marked bradycardia, the drug should be discontinued.

Chronic heart failure. Recommended initial dose of Coraxan is 10 mg per day (1 tablet of 5 mg twice a day).
After two weeks of use the daily dose of Coraxan may be increased up to 15 mg (1 tablet of 7.5 mg twice a day) if resting heart rate is stably more than 60 bpm. If HR is stable less than 50 beats/min or in case of bradycardia symptoms, such as dizziness, increased fatigability or arterial hypotension, the dose may be decreased to 2.5 mg (1/2 tablet of 5 mg) 2 times per day.
If the resting heart rate is within the range of 50-60 beats/min, it is recommended to use the preparation Coraxan in a dose of 5 mg twice a day./min or if bradycardia symptoms are noted in the patient, the drug dose should be decreased for patients receiving Coraxan in dose of 5 mg 2 times per day or 7.5 mg 2 times per day.
If resting heart rate is steadily more than 60 bpm in patients receiving Coraxan 2.5 mg (1/2 tablet of 5 mg) 2 times daily or 5 mg 2 times daily, the drug dose may be increased.
If heart rate is less than 50 bpm or if bradycardia symptoms persist, the drug should be stopped.

In patients aged 75 years and older the recommended starting dose of Coraxan is 2.5 mg (1/2 tablet of 5 mg) twice daily. Thereafter, the dose of the drug may be increased.

Renal dysfunction. Recommended dose for patients with CKD more than 15 ml/min is 10 mg per day (1 tablet 5 mg 2 times per day). Taking this medicine dose can be increased up to 15 mg (1 tablet of 7.5 mg two times per day).
Because of lack of clinical data concerning Coraxan use in patients with IQ less than 15 ml/min, the preparation should be used with caution.

Hepatic impairment. In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale) the usual dosage regimen is recommended. The recommended starting dose for Coraxan is 10 mg per day (1 tablet of 5 mg 2 times per day). After 3-4 weeks of use, depending on the therapeutic effect, the dose may be increased to 15 mg (1 tablet of 7.5 mg 2 times per day).

Interaction

Pharmacodynamic Interactions

Not recommended combinations

The QT interval prolonging drugs (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).

The non-cardiovascular QT interval lengthening drugs (e.g., pimozide, ziprasidone, certindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin by IV).

The concomitant use with drugs that prolong the QT interval may increase heart rate slowing, so close cardiac monitoring should be performed if concomitant use is necessary.

Pharmacokinetic interaction

Cytochrome P4503A4 (CYP3A4). Ivabradine is metabolized in the liver by enzymes of cytochrome P450 system (CYP3A4) and is a very weak inhibitor of this cytochrome. Ivabradine has no significant effect on the metabolism and plasma concentrations of other cytochrome CYP3A4 substrates. At the same time, CYP3A4 inhibitors and inducers interact with ivabradine and affect its metabolism and pharmacokinetic properties. CYP3A4 cytochrome inhibitors have been found to increase and CYP3A4 cytochrome inducers to decrease the plasma concentrations of ivabradine. Increased plasma concentrations of ivabradine increase the risk of marked bradycardia.

Contraindicated combinations

Concomitant use with strong cytochrome P450 inhibitors, such as antifungal agents of azole group (ketoconazole, itraconazole), antibiotics from macrolide group (clarithromycin, oral erythromycin, jozamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, ketoconazole (in a dose of 200 mg once daily) or jozamycin (in a dose of 1 g twice daily), increase average plasma concentrations of ivabradine by 7-8 times.

Not recommended combinations

Moderate CYP3A4 inhibitors. The combined use of ivabradine and the heart rate-limiting agents diltiazem or verapamil was well tolerated by patients and was accompanied by a 2-3-fold increase in ivabradine concentration, with an additional heart rate slowing of about 5 bpm.

This combination is not recommended.

Combinations requiring caution when using

Moderate CYP3A4 inhibitors. Concomitant use of ivabradine with other CYP3A4 inhibitors (e.g., fluconazole) should be started with an initial dose of 2.5 mg twice daily. If HR is less than 60 bpm, careful monitoring of HR is necessary.

Grapefruit juice. A 2-fold increase in ivabradine blood concentrations has been observed with grapefruit juice. Grapefruit juice should be minimized during therapy with ivabradine.

CYP3A4 inducers such as rifampicin, barbiturates, phenytoin and herbal preparations containing Hypericum perforatum when used together may decrease the blood concentration and activity of ivabradine and require a higher dose of ivabradine. During therapy with ivabradine, the use of drugs and products containing St. John’s wort should be minimized.

Combined use with other drugs

It has been demonstrated that there is no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine of the following drugs: Proton pump inhibitors (omeprazole, lansoprazole), phosphodiesterase-5 inhibitors (sildenafil), HMG-CoA reductase inhibitors (simvastatin), dihydropyridine-type BCA derivatives (amlodipine, lacidipine), digoxin and warfarin.

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

In the pilot phase III study, the use of the following drugs had no specific restrictions, so 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.

Special Instructions

Heart rhythm disorders
Coraxan is ineffective in the treatment or prevention of arrhythmias. Its effectiveness decreases against the background of the development of tachyarrhythmias (e.g. ventricular or supraventricular tachycardia). The drug is not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias associated with sinus node function.
During therapy, patients should be clinically monitored for atrial fibrillation (paroxysmal or permanent). If clinically indicated (e.g., worsening angina, palpitations, irregular heart rhythm), ECG should be included in ongoing monitoring.

The use in patients with bradycardia
Coraxan is contraindicated if the resting HR is less than 60 bpm before therapy. If during the treatment the resting HR falls below 50 BPM or the patient has bradycardia-related symptoms (such as dizziness, increased fatigue or hypotension), the drug dose should be decreased. If the HR remains less than 50 bpm or bradycardia-related symptoms persist when the drug dose is reduced, Coraxan should be discontinued.

Combined use as part of antianginal therapy
The use of Coraxan together with HR-relieving BMCCs such as verapamil or diltiazem is not recommended. When combining ivabradine with nitrates and dihydropyridine-type BMCCs such as amlodipine, no changes in the safety profile of the therapy have been observed. Combined use with BMCC has not been found to increase the efficacy of ivabradine.

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

Visual functions
Coraxan affects retinal function. No toxic effects of ivabradine on the retina have been identified to date, but the effects of the drug on the retina during long-term use (>1 year) are unknown to date. In case of visual impairment not described in these instructions, discontinuation of Coraxan should be considered. Coraxan should be used with caution in patients with retinal pigmentary degeneration (retinitis pigmentosa).

Auxiliary excipients
The drug contains lactose; therefore Coraxan is not recommended for patients with lactase deficiency, lactose intolerance or glucose-galactose malabsorption syndrome.

Arterial hypotension
Because of insufficient clinical data the drug should be used with caution in patients with arterial hypotension.

Atrial fibrillation (atrial fibrillation) – cardiac arrhythmias
There is no evidence of increased risk of bradycardia with Coraxan in restoring sinus rhythm during pharmacological cardioversion. However, due to insufficient data, when electrical cardioversion can be delayed, Coraxan should be discontinued 24 hours prior to cardioversion.

Performance in patients with congenital long QT interval syndrome or patients receiving drugs prolonging the QT interval
Coraxan should not be administered in congenital long QT interval syndrome and also in combination with drugs prolonging the QT interval. Strict ECG monitoring is necessary if such therapy is necessary.

Moderate hepatic impairment
Therapy with Coraxan should be performed with caution in moderate hepatic impairment (less than 9 points by Child-Pugh score).

Severe renal impairment
In severe renal impairment (CKI less than 15 ml/min), therapy with Coraxan should be used with caution.

Contraindications

Side effects

Visually:
Very common: changes in light perception (photopsia): noted in 14.5% of patients and described as a transient change in brightness in a limited area of the visual field. As a rule, such phenomena were provoked by an abrupt change of illumination intensity in the visual field zone. Generally, photopsia appeared in the first two months of treatment with subsequent recurrence. 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 occurrence of photopsia was a reason for discontinuing treatment.
Often: blurred vision.

Cardiovascular system disorders:
Often: bradycardia: in 3.3% of patients, especially during the first 2-3 months of the therapy; 0.5% of patients had severe bradycardia with heart rate not more than 40 beats/min; AV block of 1st degree; ventricular extrasystole.
Infrequent: palpitation, supraventricular extrasystole.
Unspecified frequency: arterial hypotension, possibly associated with bradycardia
The following adverse events identified in clinical trials occurred with equal frequency in both the patient group receiving ivabradine and the comparison group, suggesting their association with the disease itself and not with ivabradine administration: sinus arrhythmia; angina pectoris, including unstable angina; atrial fibrillation; myocardial ischemia; myocardial infarction; and ventricular tachycardia.

Digestive system disorders: infrequent: nausea, constipation, diarrhea.

Central nervous system disorders:
Often: headache, especially in the first month of therapy; dizziness, possibly associated with bradycardia.
Infrequent: shortness of breath, vertigo, muscle spasms.
Unspecified frequency: fainting, possibly associated with bradycardia.

Laboratory measures: infrequent: hyperuricemia, eosinophilia, increased plasma creatinine concentration.

Skin and subcutaneous fat: skin rash, itching, erythema, angioedema, urticaria.

General disorders and symptoms: asthenia, increased fatigue, malaise, possibly associated with bradycardia.

Overdose

Symptoms: severe and prolonged bradycardia.

The treatment of severe bradycardia should be symptomatic and carried out in specialized departments. If bradycardia develops in conjunction with abnormal hemodynamic parameters, symptomatic treatment with intravenous administration of beta-adrenomimetics, such as isoprenaline, is indicated.

If necessary, an artificial pacemaker may be inserted.

Pregnancy use

The drug Coraxan is contraindicated for use in pregnancy. At present, there are insufficient data on the use of the drug during pregnancy. Preclinical studies of ivabradine showed embryotoxic and teratogenic effects.

The use of Coraxan during lactation is contraindicated. There are no data on penetration of ivabradine into breast milk.

Similarities