Кораксан®

General characteristics. Structure:

Tablets, coated 1 tab. of an ivabradin hydrochloride of 5,390 mg 8,085 mg
(it is equivalent to an ivabradin in the form of the basis — 5 and 7,5 mg respectively)  
excipients: lactoses monohydrate, magnesium stearate, corn starch, maltodextrin, silicon dioxide colloid anhydrous, gipromelloza, titanium dioxide (E171), macrogoal 6000, глицерол, magnesium stearate, ferrous oxide yellow (E172), ferrous oxide red (E172)  
in the blister of 14 pieces; in a pack the cardboard 1 blister.
Description of a dosage form

Tablets of 5 mg: oval, biconvex, coated salmoncolored color, with notches from two lateral faces and an engraving on two parties. On one party — in the form of a logo of firm, on another — figure 5.
Tablets of 7.5 mg: triangular, coated salmoncolored color, with an engraving on two parties. On one party — in the form of a logo of firm, on another — figure 7,5.

Pharmacological properties:

Pharmacokinetics. Ivabradin is quickly released from tablets and very well dissolved in water (> 10 mg/ml). The molecule of an ivabradin is represented by S-enantiomer, with lack of bioconversion according to the researches in vivo. It is established that at the person the main active metabolite of drug is N-desmetilirovannoye derivative an ivabradina.
Absorption and bioavailability. It is quickly and almost completely soaked up in a GIT after intake. Cmax in a blood plasma is reached in 1,5 h after intake on an empty stomach. Bioavailability makes about 40% that is caused by effect of "the first passing" through a liver.
Meal increases absorption time approximately by 1 h and increases concentration in a blood plasma from 20 to 30%. For reduction of interindividual variability drug is recommended to be accepted during food.
Distribution. Linkng with proteins of a blood plasma — about 70%. The volume of distribution makes about 100 l. Cmax in a blood plasma after prolonged use in the recommended dose on 5 mg 2 times a day makes about 22 ng/ml (CV =29%). Average equilibrium concentration in a blood plasma makes 10 ng/ml.
Biotransformation. Ivabradin is substantially metabolized in a liver and intestines by oxidation in the presence of P4503A4 (CYP3A4) cytochrome. The main active metabolite is N-desmetilirovannoye derivative (S 18982), its part makes 40% of a dose of initial connection and is characterized by similar pharmacokinetic and pharmakodinamichesky properties. Metabolism of an active metabolite of an ivabradin also happens in the presence of CYP3A4 cytochrome.
Ivabradin has low affinity to CYP3A4 enzyme, at the same time any signs of induction or inhibition of enzyme are not noted. In this regard, it is improbable that ивабрадин changes metabolism or concentration of substrates of CYP3A4 enzyme in a blood plasma. On the other hand, the combined use of strong inhibitors or inductors of P450 cytochrome can affect considerably concentration of an ivabradin in a blood plasma (see the sections "Interaction" and "Special Instructions").
Removal. T1/2 of an ivabradin averages about 2 h (70–75% of AUC), and effective T1/2 makes 11 h. The general clearance — about 400 ml/min., and renal — about 70 ml/min. Removal of metabolites and insignificant amounts of not changed substance happens to identical speed through kidneys and a GIT. About 4% of the dose accepted inside are allocated with urine.
Linearity and nonlinearity. The pharmacokinetics of an ivabradin is linear at doses from 0,5 to 24 mg.
Special groups of patients
Advanced and senile age. Differences in such pharmacokinetic parameters both AUC, and Cmax between groups of patients are more senior than 65 years, patients 75 years are more senior and by the general population it was not observed.
Renal failure. Influence of a renal failure (creatinine Cl — 15–60 ml/min.) on kinetics of an ivabradin minimum.
Liver failure. At patients with easy degree of a liver failure (5–7 on classification of Chayld-Pyyu) AUC of an ivabradin and its active metabolite is 20% more, than at normal function of a liver.
The number of data for patients with a moderate liver failure (7–9 on classification of Chayld-Pyyu) does not allow to make the conclusion about use of an ivabradin for this group of patients.
Clinical data on use of an ivabradin for patients with a heavy liver failure (more than 9 on classification of Chayld-Pyyu) at the moment are absent.
Interrelation between pharmacokinetic and pharmakodinamichesky properties
The analysis of interrelation between pharmacokinetic and pharmakodinamichesky properties allowed to establish that the urezheniye of ChSS has direct proportionality from increase in a blood plasma of concentration of an ivabradin and an active metabolite S 18982 at dosing levels up to 15–20 mg 2 times a day. At higher doses of drug delay of a cordial rhythm has no proportional dependence with concentration of an ivabradin in a blood plasma and is characterized by a tendency to achievement of effect of the plateau. High level of concentration of an ivabradin which can be reached at a drug combination with strong inhibitors of CYP3A4 enzyme can lead to the expressed decrease in ChSS, however this risk decreases at a combination with moderate CYP3A4 inhibitors.

Pharmacodynamics. Ivabradin — the drug which is slowing down a heart rhythm which mechanism of action consists in the selection and specific suppression of the If-channels of a sinus node controlling spontaneous diastolic depolarization in a sinus node and regulating ChSS.
Influence on cordial activity is specific to a sinus node, does not affect time of carrying out impulses on intra atrial, atrioventricular and intra ventricular conduction paths, and also sokratitelny ability of a myocardium. Processes of repolarization of ventricles are left without change.
Ivabradin can also interact with the Ih-channels of a retina of an eye similar to the If-channels of heart participating in emergence of temporary change of system of visual perception due to change of reaction of a retina to bright light incentives.
Under provocative circumstances (for example bystry change of brightness) the partial inhibition of Ih-channels ivabradiny causes a so-called phenomenon of change a svetovospriyatiya (photopsia). The taking place change of brightness in limited area of the visual field is characteristic of a photopsia.
The main pharmacological feature of an ivabradin is its ability of dozozavisimy decrease in ChSS. The analysis of dependence of size of decrease in ChSS on a dose of drug was carried out at gradual increase in a dose of an ivabradin up to 20 mg 2 times a day and revealed a tendency to achievement of effect of the plateau (lack of increase of therapeutic effect) that reduces risk of development of heavy, badly transferable bradycardia (ChSS — <40 уд. / mines).
At purpose of drug in the recommended doses the urezheniye of ChSS makes about 10 уд. / mines at rest and at an exercise stress. As a result cardiac performance decreases and the need of a myocardium for oxygen decreases.

Clinical pharmacology

Ivabradin does not influence endocardiac conductivity, sokratitelny ability (there is no negative inotropic effect) or process of repolarization of ventricles:
- in clinical electrophysiologic trials ивабрадин did not exert impact on time of carrying out impulses on atrioventricular or intra ventricular conduction paths, and also on the corrected QT intervals;
- in special researches with participation more than 100 patients with dysfunction of a left ventricle (fraction of emission of 30-45%) were shown that ивабрадин does not influence sokratitelny function of a myocardium.
Anti-anginal and anti-ischemic efficiency of an ivabradin was shown in 4 double blind people, randomized researches (2 researches — placebo controlled and 2 — comparative, with atenololy and amlodipiny). 3 222 patients with chronic stable stenocardia from whom 2 168 received ивабрадин participated in these researches.
It is established that ивабрадин in a dose of 5 mg 2 times a day exerted beneficial effect on all indicators of load tests already in 3–4 weeks of therapy. Efficiency was confirmed also for a dose of 7,5 mg 2 times a day. In particular, the additional effect at increase in a dose from 5 to 7,5 mg 2 times a day was established in a comparative research with atenololy: time of performance of an exercise stress increased approximately for 1 min. in 1 month of use of an ivabradin in a dose of 5 mg 2 times a day, thus after additional 3-month reception of an ivabradin in a dose of 7,5 mg 2 times a day the further gain of this indicator on 25 pages is noted. In this research anti-anginal and anti-ischemic efficiency of an ivabradin was confirmed also for patients at the age of 65 years and is more senior. Efficiency of an ivabradin in doses of 5 and 7,5 mg 2 times a day was noted in the specified researches concerning all indicators of load tests (the general duration of an exercise stress, time to the limiting stenocardia attack, time prior to the beginning of an attack of stenocardia and time before development of a depression of a segment of ST for 1 mm, is lower than the isoline), and also was followed by reduction of frequency of development of attacks of stenocardia approximately for 70%. The dosing mode with 2-fold use of an ivabradin within a day allowed to provide equal efficiency for 24 h.
Randomized placebo - a controlled research with participation of 725 patients did not show any additional efficiency of an ivabradin at accession to the maximum dose of an amlodipin on recession of therapeutic activity (in 12 h after intake) while at the peak of activity (in 3–4 h after intake) additional efficiency of an ivabradin was proved. In researches of clinical performance of drug, effects of an ivabradin completely remained throughout 3-and 4-month periods of treatment. During treatment signs of pharmacological tolerance (decrease in efficiency) were absent, and after the termination of treatment of a withdrawal it was not noted. Anti-anginal and anti-ischemic effects of an ivabradin were connected with dozozavisimy decrease in ChSS, and also with considerable reduction of the working work (ChSS × GARDEN), and both at rest, and at an exercise stress. Influence on the ABP level and resistance of peripheral vascular system was insignificant and clinically not expressed.
Steady decrease in ChSS was shown at the patients accepting ивабрадин at least during 1 year (n = 713). No influence on metabolism of glucose or lipids at the same time was observed.
At patients with a diabetes mellitus (n = 457) ивабрадин efficiency and safety, as well as at other, comparable groups of patients on number shows.

Indications to use:

Treatment of stable stenocardia at patients with a normal sinoatrial rate at intolerance or contraindications to use of beta adrenoblockers.

Route of administration and doses:

Inside, with the 2-hkratny mode of dosing within a day, i.e. in the morning and in the evening during food.
The usual recommended starting dose of drug Koraksan makes 10 mg/days (1 tab. on 5 mg 2 times a day). Depending on therapeutic effect, in 3–4 weeks of use the dose of drug can be increased to 15 mg (1 tab. on 7,5 mg 2 times a day). If against the background of therapy size ChSS decreases to values less than 50 уд. / mines or the patient has symptoms connected with bradycardia (such as dizziness, fatigue or arterial hypotension), it is necessary to pick up lower dose of drug. If at Koraksan dose decline size ChSS is not normalized and remains at the level of less than 50 ud. / min., then administration of drug should be cancelled.
Use for elderly people. Koraksan's use for patients of 75 years is also more senior 2 times a day were studied at the limited number of patients therefore for this age group it is recommended to begin treatment with an initial dose of 2,5 mg (1/2 tab. on 5 mg), increase in a daily dose depending on a condition of the patient is possible.
Renal failure. At creatinine Cl higher than 15 ml/min. are recommended the usual mode of dosing.
Because of a lack of clinical data on Koraksan's use at creatinine Cl lower than 15 ml/min. drug should be taken with caution.
Liver failure. Any change of the mode of a drug dosing at easy degree of a liver failure is not required. It is necessary to be careful at moderate degree of a liver failure. At heavy degree of a liver failure administration of drug is contraindicated as at this group of patients researches were not conducted.

Features of use:

Cardiac arrhythmia
Koraksan is not effective for treatment or prevention of cardiac arrhythmias. Its efficiency falls against the background of development of a tachyarrhythmia (for example ventricular or supraventricular tachycardia). Also Koraksan is not recommended to patients with the fibrillation of auricles (ciliary arrhythmia) or other types of arrhythmias connected with function of a sinus node.
At therapy by Koraksan it is recommended to carry out regular control regarding development of fibrillation of auricles (paroxysmal or constant). At clinical indications (for example at the complicated stenocardia, the expressed heartbeat, the irregularity of a cordial rhythm) should include the electrocardiogram (ECG) in the current control.
AV blockade of the II degree. Koraksan is not recommended for treatment at AV to blockade of the II degree.
Use for patients with low size ChSS. Koraksan is not recommended to the patients having before purpose of drug ChSS lower than 60 уд. / min.
If against the background of therapy size ChSS decreases to values less than 50 уд. / mines or the patient has symptoms connected with bradycardia (such as dizziness, fatigue or arterial hypotension), it is necessary to pick up lower dose of drug. If at Koraksan dose decline size ChSS is not normalized and remains at the level of less than 50 ud. / min., then administration of drug should be cancelled.
The combined use as a part of anti-anginal therapy. Koraksan's use together with BKK which are slowing down ChSS, such as verapamil or diltiazem is not recommended.
At the combined Koraksan's use with nitrates, BKK derivative a dihydropyridinic row (such as амлодипин) no influence on safety and efficiency was revealed.
Chronic heart failure. Before Koraksan's appointment the patient has to be inspected on existence of chronic heart failure. In the presence of chronic heart failure of a functional class III-IV (on NYHA classification) Koraksan is contraindicated due to the lack of enough data on efficiency and safety of use of drug. Because of the insufficient number of the inspected patients it is necessary to appoint drug with care at symptomless dysfunction of a left ventricle and at chronic heart failure of a class II (on NYHA classification).
Stroke. It is not recommended to appoint drug right after the had stroke since there are no data on its use during this period.
Functions of visual perception (Visual function). Koraksan affects function of a retina of an eye. There are no proofs of toxic action of an ivabradin on a mesh cover of an eye now. Effects of action of Koraksan on a retina at prolonged use are not known today. At emergence of the disturbances of visual functions which are not described in the instruction it is necessary to consider a question of the termination of reception of Koraksan. Drug should be taken with caution to patients with a pigmental degeneration of a retina (retinitis pigmentosa).
Excipients. Lactose therefore to patients with intolerance of a galactose, deficit of Lapp lactase or glyukogalaktozny absorption administration of drug Koraksan is not recommended is a part of excipients of drug.
Arterial hypotension. Because of the insufficient number of clinical data Koraksan patients should appoint with care with soft and moderate degree of arterial hypotension.
Koraksan is contraindicated at heavy arterial hypotension (DAD lower than 90 mm hg and the GARDEN lower than 50 mm hg);
Fibrillation of auricles (ciliary arrhythmia) — cardiac arrhythmias
There are no proofs of risk of development of bradycardia against the background of Koraksan's reception at recovery of a sinoatrial rate during pharmacological cardioversion. Nevertheless, due to the lack of enough data at an opportunity to delay DC cardioversion Koraksan's reception should be stopped for 24 h before its carrying out.
Use for patients with an inborn syndrome of the extended interval of QT or patients accepting the means extending QT interval.
Koraksan it is not necessary to appoint at an inborn syndrome of the extended QT interval, and also at a combination with the drugs which are slowing down QT interval. At impossibility to avoid therapy by Koraksan it is necessary to carry out careful cardiocontrol.
Moderate liver failure. At a moderate liver failure therapy by Koraksan should be carried out with care.
Heavy renal failure. At a heavy renal failure (creatinine Cl <15 ml/min.) therapy by Koraksan should be carried out with care.
Influence on ability to manage vehicles and to perform the works demanding the high speed of psychomotor reactions. It was shown that generally Koraksan's use does not influence ability of driving, but in connection with a possibility of emergence of a photopsia it is necessary to show care at control of vehicles and/or performance of the work demanding the high speed of psychomotor reactions.

Side effects:

When studying Koraksan's in clinical trials of the II-III phase about 5000 patients were inspected. Koraksan more than 2 900 patients received.
Disturbances of visual perception it is very frequent (> 1/10) — a phenomenon of change of photoperception (photopsia): it was noted at 14,5% of patients and it was described as the taking place change of brightness in a limited zone of the visual field. As a rule, the similar phenomena were initiated by sharp change of intensity of lighting. Generally the photopsia appeared in the first 2 months of treatment with the subsequent repetition and had poorly or moderately expressed intensity. Emergence of a photopsia stopped as after completion of therapy, so, in most cases (77,5%), and during its carrying out. Only at 1% of patients emergence of a photopsia was a cause of failure from treatment or change of a usual daily routine. Often (> 1/100, <1/10) — a sight vagueness.
From cardiovascular system: often (> 1/100, <1/10) — bradycardia (at 3,3% of patients, especially in the first 2–3 months of therapy; at 0,5% of patients heavy bradycardia with ChSS below or equivalent 40 уд. / mines developed); AV blockade of the I degree; ventricular premature ventricular contraction. Sometimes (> 1/1000, <1/100) — heartbeat, supraventricular premature ventricular contraction.
The following states revealed in the course of clinical trials arose with an identical frequency as in group of the patients receiving ивабрадин and in group of comparison that assumes communication with disease per se, but not with reception of an ivabradin: sinus arrhythmia, unstable stenocardia, deterioration in a course of stenocardia, ciliary arrhythmia, myocardium ischemia, myocardial infarction and ventricular tachycardia.
From a GIT: sometimes (> 1/1000, <1/100) — nausea, a lock, diarrhea.
General disturbances: often (> 1/100, <1/10) — a headache, especially in the first month of therapy; the dizziness which is perhaps connected with bradycardia; sometimes (> 1/1000, <1/100) — dizziness; asthma; muscular spasms.
Laboratory indicators: sometimes (> 1/1000, <1/100) — a hyperuricemia; eosinophilia; increase in level of creatinine in a blood plasma.

Interaction with other medicines:

Pharmakodinamichesky interaction
Not recommended combinations
The HP extending QT interval (for example quinidine, Disopyramidum, bepridit, соталол, ибутилид, Amiodaronum).
The HP extending QT an interval which are not relating to cardiovascular means (for example Pimozidum, зипразидон, сертиндол, мефлохин, галофантрин, pentamidine, цизаприд, erythromycin in/in).
Combined use with the drugs extending QT interval can strengthen urezheny ChSS therefore in need of joint appointment it is necessary to carry out careful cardiocontrol.
Pharmacokinetic interaction
P 450 3A4 cytochrome (CYP3A4). Ivabradin is metabolized in a liver by enzymes of system of P450 (CYP3A4) cytochrome and is very weak inhibitor of this cytochrome. Ivabradin has no significant effect on metabolism and concentration in a blood plasma of other substrates of CYP3A4 cytochrome. At the same time, inhibitors and the inductors CYP3A4 enter interaction with ivabradiny and influence his metabolism and pharmacokinetic properties. It was established that inhibitors of CYP3A4 cytochrome raise, and inductors of CYP3A4 cytochrome reduce plasma concentration of an ivabradin. Increase in concentration of an ivabradin in a blood plasma increases risk of development of the expressed bradycardia.
Contraindicated combinations
Simultaneous use with strong inhibitors of P 450 cytochrome, such as antifungal means of group of azoles (кетоконазол, интраконазол), antibiotics from group of macroleads (кларитромицин, erythromycin peroral, джозамицин, телитромицин), inhibitors of HIV proteases (нелфинавир, ритонавир) and нефазодон, кетоконазол (in a dose of 200 mg of 1 times a day) or джозамицин (in a dose of 1 g 2 times a day), increase average concentration of an ivabradin in a blood plasma by 7–8 times.
Not recommended combinations
CYP3A4 inhibitors of moderate action.
The combined use of an ivabradin and means, urezhayushchy ChSS, diltiazem or verapamil, was well transferred by patients and was followed by increase in concentration of an ivabradin by 2–3 times, at the same time the additional urezheniye of ChSS made about 5 уд. / min.
This combination is not recommended.
The combinations demanding care at use
CYP3A4 inhibitors of moderate action. Simultaneous use of an ivabradin with other CYP3A4 inhibitors (for example флуконазол) has to begin with an initial dose of 2,5 mg 2 times a day. At ChSS is more rare 60 уд. / mines careful control of ChSS is necessary.
Grapefruit juice. Against the background of reception of grapefruit juice increase in concentration of an ivabradin in blood was noted twice. During therapy ivabradiny reception of the grapefruit juice and a St. John's Wort which is made a hole has to be reduced to a minimum.
The inductors CYP3A4, such as rifampicin, the barbiturates, Phenytoinum and vegetable drugs containing a St. John's Wort made a hole (Hypericum perforatum) at combined use can lead to decrease in concentration in blood and activity of an ivabradin and to demand selection of higher dose of an ivabradin. During therapy ivabradiny use of the drugs and products containing the St. John's Wort which is made a hole has to be reduced to a minimum.
The combined use with other medicines
Lack of clinically expressed effect on a pharmacodynamics and pharmacokinetics of an ivabradin of the following HP was shown: inhibitors of a proton pomp (омепразол, лансопразол), inhibitors of phosphodiesterase-5 (sildenafit), GMG-KOA-reduktazy inhibitors (симвастатин), BKK derivative a dihydropyridinic row (амлодипин, лацидипин), digoxin and a varfavin.
It is shown what ивабрадин does not render clinically expressed effect on pharmacokinetics of a simvastatin, amlodipin, latsidipin, pharmacokinetics and a pharmacodynamics of digoxin, a varfavin and on a pharmacodynamics of acetylsalicylic acid.
In a pilot research III of a phase use of the medicines provided below had no special restrictions in this connection they can be appointed in a combination with ivabradiny without special precautionary measures: APF inhibitors, antagonists of AT II of receptors, diuretics, nitrates of the short and prolonged action, inhibitors of GMG-KOA-reduktazy, a fibrata, inhibitors of a proton pomp, peroral hypoglycemic means, acetylsalicylic acid and other antitrombotichesky means.

Contraindications:

hypersensitivity to an ivabradin or any of drug excipients;
ChSS at rest is lower than 60 beats/min (prior to treatment);
cardiogenic shock;
acute myocardial infarction;
the expressed arterial hypotension (the GARDEN — is lower than 90 mm hg and DAD — lower than 50 mm hg);
heavy liver failure (more than 9 on classification of Chayld-Pyyu);
sick sinus syndrome;
sinuatrial blockade;
chronic heart failure of the III-IV stage on NYHA classification (due to the lack of enough clinical data);
existence of an artificial pacemaker;
unstable stenocardia;
AV blockade of the III degree;
simultaneous use with such strong inhibitors of P 4503A4 cytochrome as antifungal means of group of azoles (кетоконазол, интраконазол), antibiotics from group of macroleads (кларитромицин, erythromycin for intake, джозамицин, телитромицин), inhibitors of HIV proteases (нелфинавир, ритонавир) and нефазодон;
pregnancy;
feeding period breast;
children's age (up to 18 years) (efficiency and safety of its use for this age group was not studied).

Use at pregnancy and feeding by a breast

At the moment there are no data relating to Koraksan's use for pregnant women. In researches of influence of drug on reproductive function at animals embriotoksichny and teratogenic effects of drug were shown. The potential risk of influence on reproductive function at the person is not established. Thus, Koraksan is contraindicated for use at pregnancy.
In researches on animals it is established what ивабрадин is allocated with breast milk. In this regard Koraksan's use during feeding by a breast contraindicated.
Use for children and teenagers. Koraksan is not recommended to use drug at children and teenagers up to 18 years as efficiency and safety of its use for this age group was not studied.

Overdose:

Symptoms: development of the heavy long bradycardia which is badly transferred by patients.
Treatment: symptomatic, is carried out in specialized departments. In case of development of bradycardia in combination with adverse changes of indicators of a hemodynamics the symptomatic treatment with intravenous administration of beta-adrenergic agonists, such as изопреналин is shown. If necessary it is necessary to consider the possibility of temporary installation of an artificial pacemaker.

Storage conditions:

Special storage conditions are not required. To store in the place, unavailable to children. Period of validity 3 years.

Issue conditions:

According to the recipe

Packaging:

According to 14 tab. in the blister (PVC / Is scarlet). On 1, 2 or 4 blisters with the instruction on a medical use in a pack cardboard.

When packaging (packaging) at the Russian enterprise LLC Serdiks:

According to 14 tab. in the blister (PVC / Is scarlet). On 1, 2 or 4 blisters with the instruction on a medical use in a pack cardboard.