KORAKSAN
Active material: Ivabradine
When ATH: C01EB17
CCF: Antianginal drug. Selective inhibitor of If-channel sinus
ICD-10 codes (testimony): i20
When CSF: 01.12.06
Manufacturer: Laboratories servant (France)
Pharmaceutical form, composition and packaging
Pills, coated orange-pink, Oval, lenticular, notched on both sides and on both sides of engraving (on one side – company logo, another – figure “5”).
| 1 tab. | |
| ivabradine hydrochloride | 5.39 mg, |
| that respectively. content ivabradine | 5 mg |
Excipients: lactose monohydrate, magnesium stearate, corn starch, maltodextrin, Colloidal anhydrous silica, gipromelloza, Titanium dioxide (E171), macrogol 6000, glycerol, iron oxide yellow (E172), iron oxide red (E172).
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
Pills, coated orange-pink, Triangular, engraved on both sides (on one side – company logo, another – number “7.5”).
| 1 tab. | |
| ivabradine hydrochloride | 8.085 mg, |
| that respectively. content ivabradine | 7.5 mg |
Excipients: lactose monohydrate, magnesium stearate, corn starch, maltodextrin, Colloidal anhydrous silica, gipromelloza, Titanium dioxide (E171), macrogol 6000, glycerol, iron oxide yellow (E172), iron oxide red (E172).
14 PC. – blisters (1) – packs cardboard.
14 PC. – blisters (2) – packs cardboard.
14 PC. – blisters (4) – packs cardboard.
Pharmacological action
Antianginal drug. The mechanism of action is selective and specific inhibition of the sinus node If channels, controlling spontaneous diastolic depolarization in the sinus node and regulating heart rate.
Effect on cardiac function specific to the sinus node, It does not affect the duration of the pulses of intraatrial, atrioventricular and intraventricular conduction paths, and the myocardial contractility. Ventricular repolarization process remain unchanged.
Ivabradine can interact also with IhTV retina, If similar to the channels of the heart, involved in the occurrence of a temporary change of visual perception by changing the reaction of the retina to bright light stimuli.
When precipitating circumstances (eg, rapid change of brightness) partial inhibition of Ih channels ivabradine is the so-called phenomenon of change svetovospriyatiya (photopsia). For photopsias characteristically undergoing change brightness in a limited area of the visual field.
The main pharmacological characteristics of ivabradine is its ability to dose-dependent reduction in heart rate. Analysis of the dependence of the reduction in heart rate of dose was carried out by gradually increasing the dose of ivabradine up 20 mg 2 times / day, and showed a tendency to achieve a plateau effect (the lack of increase therapeutic effect), which reduces the risk of severe, poorly tolerated bradycardia (HR less 40 u. / min).
In appointing the drug at the recommended doses, slowing of heart rate is approximately 10 u. / min at rest and during exercise. This reduces the work of the heart and decreases myocardial oxygen demand.
Ivabradine does not influence intracardiac conduction, contractility (It does not cause negative inotropic effect) or the process of ventricular repolarization. In clinical electrophysiology studies, ivabradine had no effect on the time of the pulses on the atrioventricular or intraventricular conduction paths, as well as the corrected QT intervals. In special studies involving more 100 patients with left ventricular dysfunction (ejection fraction 30-45%) It demonstrated, that ivabradine does not affect myocardial contractility.
Antianginal and antiischemic efficacy of ivabradine has been demonstrated in 4 double-blind, randomized trials (2 placebo-controlled studies and 2 Comparative studies with atenolol and amlodipine). In these studies involved 3222 patients with chronic stable angina, of which 2168 received ivabradine.
Established, that ivabradine at a dose 5 mg 2 times / day has a beneficial effect on all indicators of stress tests within 3-4 weeks of therapy. Efficacy was confirmed and the dose 7.5 mg 2 times / day. In particular, additional effect with increasing dose 5 mg 7.5 mg 2 times / day was set in a comparative study with atenolol. Time of exercise increased by about 1 minutes after 1 month use at a dose of ivabradine 5 mg 2 times / day, wherein after additional 3-month receiving ivabradine at a dose 7.5 mg 2 times / day marked by a further increase in this indicator on 25 sec. In this study, antianginal and antiischemic efficacy of ivabradine was confirmed for patients aged 65 and older. Efficacy of ivabradine when used in doses 5 mg 7.5 mg 2 times / day was observed in these studies with regard to all indicators load tests (the total duration of exercise, time to limiting angina attack, time before the attack of angina and time to ST depression 1 mm below the contour), and was accompanied by a decrease in the frequency of angina attacks around 70%. The dosage regimen with the use of ivabradine 2 times / day ensures equal efficacy throughout 24 no.
A randomized, placebo-controlled study involving 725 patients did not show any additional effectiveness of ivabradine in acceding to the maximum dose of amlodipine on the decline of therapeutic activity (through 12 hours after ingestion), while on the peak of activity (through 3-4 hours after ingestion) Additional efficacy of ivabradine has been proven. In clinical efficacy studies, the effects of ivabradine fully maintained throughout 3- and 4-month treatment periods. During the treatment of the signs of pharmacological tolerance absent, and after cessation of treatment withdrawal were noted. Antianginal and anti-ischemic effects of ivabradine were associated with dose-dependent reduction in heart rate, as well as a significant decrease in working works (Heart rate × systolic blood pressure), both alone, and during exercise. The impact on the value of blood pressure and systemic vascular resistance were minor and not clinically severe.
The steady decrease in heart rate was demonstrated in patients, taking ivabradine for at least 1 year (n=713). No effect on the metabolism of glucose or lipids is not observed.
In patients with diabetes (n=457) ivabradine demonstrated efficacy and safety, as other, comparable in size, groups of patients.
Pharmacokinetics
Pharmacokinetics of ivabradine is linear at doses ranging from 0.5 to 24 mg.
Ivabradine is very soluble in water (>10 mg / ml). The molecule is represented ivabradine S-enantiomer of the lack bioconversion (According to studies in vivo). Established, that human primary active metabolite of the drug is a derivative of N-desmetilirovannoe ivabradine.
Absorption
After oral administration, ivabradine is rapidly released from tablets, and then rapidly and almost completely absorbed from the gastrointestinal tract.
Cmax plasma levels achieved after 1.5 hours after ingestion on an empty stomach. Bioavailability is approximately 40%, due to the effect of “first pass” through the liver.
Eating increases the absorption by approximately 1 h and increases the concentration in blood plasma 20% to 30%. To reduce the interindividual variability is recommended to take the drug during meals.
Distribution
Binding to plasma proteins is approximately 70% .Vd is about 100 l. Cssmaxin the blood plasma after prolonged use at the recommended dose of 5 mg 2 times / day is about 22 ng / ml (CV=29%). Average Css in plasma is 10 ng / ml.
Metabolism
Ivabradine largely metabolized in the liver and intestine by oxidation in the presence of CYP3A4. The major active metabolite is the N-derivative desmetilirovannoe (S18982), part of 40% doses of the parent compound and is characterized by similar pharmacokinetic and pharmacodynamic properties. The metabolism of the active metabolite of ivabradine also occurs in the presence of CYP3A4.
Ivabradine has low affinity to CYP3A4, wherein any signs of induction or enzyme inhibition is not observed. In this regard, it is unlikely, ivabradine that alters metabolism or CYP3A4 substrate concentrations in plasma. On the other hand, the combined use of strong inhibitors or inducers of cytochrome P450 isozymes may significantly affect the concentration of ivabradine plasma.
Deduction
T1/2 ivabradine averages about 2 no (70-75% AUC) and effective T1/2 is 11 no. Total clearance – about 400 ml / min, kidney – about 70 ml / min. Excretion of metabolites and minor amounts of unchanged substance occurs at the same rate through the gastrointestinal tract and the kidneys. About 4% of an oral dose is excreted in the urine.
Pharmacokinetics in special clinical situations
These pharmacokinetic parameters such as AUC, and the value of Cmax plasma had no significant difference in patients over 65 years, senior 75 years and the general population.
Effect of renal failure (in KK from 15 to 60 ml / min) on the kinetics of ivabradine is minimal.
In patients with mild hepatic insufficiency (5-7 points on the Child-Pugh) Ivabradine AUC and ego aktivnogo metabolites 20% better, than with normal hepatic function.
The amount of data for patients with moderate (7-9 points on the Child-Pugh) hepatic impairment does not allow to conclude that the use of ivabradine in this group of patients. Clinical data on the use of ivabradine in patients with severe (more 9 points on the Child-Pugh) hepatic impairment are not currently available.
The relationship between the pharmacokinetic and pharmacodynamic properties
Analysis of the relationship between pharmacokinetic and pharmacodynamic properties it possible to establish, that the slowing of the heart rate is directly proportional to the increase in plasma concentrations of ivabradine and the active metabolite S18982 at dosage levels up to 15-20 mg 2 times / day. Using the drug in higher doses, slowing of the heart rate is not proportional to the concentrations of ivabradine plasma and is characterized by a tendency to achieve a plateau effect. The high level of concentration of ivabradine, which can be achieved by combining the drug with potent inhibitors of CYP3A4, can lead to a marked reduction in heart rate, but this risk is reduced by combination with inhibitors of CYP3A4 moderate.
Testimony
- Treatment of stable angina pectoris in patients with normal sinus rhythm in case of intolerance or contraindication to the use of beta-blockers.
Dosage regimen
Drug therapy Coraxan® It is recommended as an alternative for the symptomatic treatment of stable angina pectoris in patients with normal sinus rhythm in case of intolerance or contraindication to the use of beta-blockers.
Tablets Coraxan® intended for ingestion 2 times / day in the morning and evening during meals.
The average recommended initial dose Coraxan® is 10 mg / day (1 tab. 5 mg 2 times / day). Depending on the therapeutic effect after 3-4 weeks of the drug dose may be increased to 15 mg / day (1 tab. 7.5 mg 2 times / day).
If the value of the therapy in heart rate drops to less than 50 u. / min or the patient, symptoms, associated with bradycardia (such as dizziness, fatigue or hypotension), necessary to choose a lower dose. If dose reduction Coraxan® the value of the heart rate returns to normal and remains at less than 50 u. / min, the drug should be discontinued.
Application Coraxan® in patients 75 and older It has been studied in a limited number of patients, therefore, for this age group it is recommended to start treatment with an initial dose 2.5 mg (1/2 tab. by 5 mg) 2 times / day. Subsequently, the daily dose may be increased depending on the condition of the patient.
In patients with impaired renal function in CC > 15 ml / min recommended normal dosage.
Due to the lack of clinical data CC < 15 ml / min the drug should be used with caution.
You do not need any change in dose regimen of the drug in mild hepatic insufficiency. Caution must be exercised moderate hepatic insufficiency. At severe hepatic insufficiency the drug is contraindicated, because in this group of patients not examined.
Side effect
In the study Coraxan® in clinical trials phase II-III were surveyed about 5000 patients. Koraksan® received more than 2900 patients.
On the part of the organ of vision: Often (>1/10) – the phenomenon of change svetovospriyatiya (photopsia), I observed in 14.5% patients and was described as undergoing change brightness in a limited area of the visual field. Usually, such events were initiated by a sharp change in light intensity. Primarily, photopsia appears in the first 2 months of treatment followed by a repetition and had mild or moderate intensity. The emergence photopsias stopped after the completion of therapy, So, In most cases (77.5%), and during its implementation. Only 1% patients photopsias appearance caused the refusal of treatment or change the normal daily routine. Often (>1/100, <1/10) – blurred vision.
Cardio-vascular system: often (>1/100, <1/10) – bradycardia (3.3% patients, particularly in the first 2-3 months of therapy; in 0.5% patients developed severe bradycardia with a heart rate less than or equivalent 40 u. / min), AV block I degrees, ventricular premature beats; sometimes (>1/1000, <1/100) – heartbeat, supraventricular arrhythmias. The following state, identified in the course of clinical trials, occurred with equal frequency in patients, poluchayushtih ivabradine, and in the comparison group, that suggests a connection with the disease as such, and not with the reception of ivabradine: sinus arrhythmia, unstable angina, worsening of angina, atrial fibrillation, myocardial ischemia, myocardial infarction and ventricular tachycardia.
From the digestive system: sometimes (>1/1000, <1/100) – nausea, constipation, diarrhea.
From the body as a whole: often (>1/100, <1/10) – headache (particularly in the first month of treatment), dizziness, possibly related to bradycardia; sometimes (>1/1000, <1/100) - Dizziness, breathlessness, muscle cramps.
From the laboratory parameters: sometimes(>1/1000, <1/100) - Hyperuricemia, eozinofilija, increased creatinine in blood plasma.
Contraindications
- Resting heart rate below 60 u. / min (before treatment);
- Cardiogenic shock;
- Acute myocardial infarction;
- Severe hypotension (systolic BP below 90 mmHg. and diastolic BP below 50 mmHg.);
- Severe hepatic impairment (more 9 points on the Child-Pugh);
- SSS;
- Sinoatrialynaya blockade;
- Chronic heart failure III and IV functional class NYHA classification (due to the lack of sufficient clinical data);
- The presence of pacemaker;
- Unstable angina;
— AV block III degree;
- Simultaneous use with strong CYP3A4 inhibitors, such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, dzhozamitsin, telithromycin), HIV protease inhibitors (Nelfinavir, ritonavir) and nefazodone;
- Hypersensitivity to ivabradine or to any component of the drug.
Pregnancy and lactation
Koraksan® contraindicated during pregnancy. Currently, there are no data, relating to the use of Coraxan® in pregnant women. IN experimental research reproductive function in animals have shown embryotoxic and teratogenic effects of the drug. The potential risk of effects on reproductive function in humans is not installed.
IN experimental research found, that ivabradine is excreted in breast milk. In this regard, the use of Coraxan® lactation (breast-feeding) contraindicated.
Cautions
Koraksan® is not effective for the treatment or prophylaxis of cardiac arrhythmias. Its effectiveness is falling on the background of the development of tachyarrhythmias (eg, ventricular or supraventricular tachycardia).
Koraksan® not recommended for patients with atrial fibrillation (atrial fibrillation) or other types of arrhythmias, associated with sinus node function.
In therapy coraxan® recommended regular monitoring of the patient for the development of atrial fibrillation (paroxysmal or permanent). In clinical indications (eg, in complicated angina, expressed heartbeat, Arrhythmia) should regularly monitor the ECG.
Koraksan® not recommended in patients with AV-block II degree.
Application Coraxan® together with the calcium channel blocker, slowing down the heart rate (verapamil or diltiazem), not recommended.
When using Coraxan® with nitrates, calcium channel blockers - dihydropyridine derivatives (Takima how amlodipine) no effect on the safety and efficacy of therapies have been identified.
Before the appointment Coraxan® the patient should be evaluated for the presence of chronic heart failure. If you have chronic heart failure III and IV functional class NYHA classification Coraxan® is contraindicated due to lack of sufficient data about the efficacy and safety of the drug. Due to an insufficient number of patients studied drug should be prescribed with caution in asymptomatic left ventricular dysfunction and congestive heart failure functional class II of NYHA classification.
Not recommended to prescribe the drug immediately after stroke, tk. There are no data on its use in a given period.
Koraksan® It acts on the function of the retina. Currently, there is no evidence of toxic effect of ivabradine on the retina, and the effects of prolonged use Coraxan® against the retina to date unknown. If you have not described in the instructions of the visual functions should consider discontinuation of Coraxan®. The drug should be used with caution in patients with retinitis pigmentosa.
The preparation includes lactose, so patients with lactose intolerance, lactase deficiency or malabsorption of glucose and galactose, the drug Coraxan® not recommended.
Because of the lack of clinical data Coraxan® should be used with caution in patients with mild to moderate hypotension.
By drinking grapefruit juice during treatment with Coraxan® there was an increase in blood concentrations of ivabradine in 2 times. During therapy receiving ivabradine grapefruit juice and St. John's wort preparations should be kept to a minimum.
There is no evidence of risk of bradycardia in patients receiving Coraxan® in restoring sinus rhythm during pharmacological cardioversion. Nonetheless, due to lack of sufficient data where possible should delay cardioversion, and the reception Coraxan® should be discontinued 24 hours before the event.
Use in Pediatrics
The drug Coraxan® It is not recommended in children and adolescents under the age of 18 years, since the efficacy and safety of its use in this age group has not been studied.
Effects on ability to drive vehicles and management mechanisms
It has been shown, that basically use Coraxan® It does not affect the ability to drive a car, but due to the possibility of occurrence photopsias patient care should be taken during the occupation of potentially hazardous activities, requiring a high rate of psychomotor reactions.
Overdose
Symptoms: Heavy prolonged bradycardia, poorly tolerated by patients.
Treatment: severe bradycardia should be symptomatic and carried out in specialized units. In the case of bradycardia combined with unfavorable changes in hemodynamic parameters shown symptomatic treatment with a / in the introduction of beta-agonists (Isoprenaline). If necessary, consider the possibility of a temporary pacemaker installation.
Drug Interactions
In a joint application with the drug Coraxan® drugs, prolonging the QT interval (quinidine, disopyramide, bepridil, sotalol, iʙutilid, Amiodarone, pimozid, ziprasidon, sertindole, mefloxin, galofantrin, pentamidine, cisapride, Erythromycin in /), may increase heart rate deceleration, so if you need a joint appointment should be careful monitoring of the cardiovascular system (such combinations is not recommended).
Ivabradine metaboliziruetsya in baked izofermentom CYP3A4 and yavlyaetsya ocheny slabыm ingibitorom dannogo izofermenta. Ivabradine has no significant effect on the metabolism and plasma concentrations of other substrates of CYP3A4. Meanwhile inhibitors and inducers of CYP3A4 interact with ivabradine and its effect on the metabolism and pharmacokinetic properties. It was found, Inhibitors of CYP3A4 increase, and inducers of CYP3A4 decrease the concentration of ivabradine plasma. Increasing concentrations of ivabradine plasma increases the risk of severe bradycardia.
Concomitant use with potent inhibitors of cytochrome P450 isoenzymes, such as azole antifungals (ketoconazole 200 mg 1 time / day), itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, dzhozamitsin /1 g 2 times / days /, telithromycin), HIV protease inhibitors (Nelfinavir, ritonavir), nefazodone increase ivabradine mean concentrations in plasma 7-8 time (Such combinations are contraindicated).
The combined use of ivabradine and funds, slows heart rate, diltiazem or verapamil is well tolerated and accompanied by an increase in the concentration of ivabradine 2-3 times, thus further slowing of the heart rate was approximately 5 u. / min (this combination is not recommended).
Concomitant use Coraxan® and a moderate CYP3A4 inhibitor action (eg, flukonazola) It can lead to a significant slowing of the heart rate (reception Coraxan® should start with a dose of 2.5 mg 2 times / day, and if the heart rate of less than 60 u. / min requires careful medical supervision.
CYP3A4 inductors, such as rifampicin, barbiturates, phenytoin, and herbal preparations, containing St. John's wort (Hypericum perforatum), when combined with coraxan® may reduce the blood concentration and activity of ivabradine and require the application of the drug at a higher dose.
In a joint application was demonstrated by the absence of clinically pronounced effect on the pharmacokinetics and pharmacodynamics of ivabradine following medicines: proton pump inhibitors (omeprazole, lansoprazole), inhibitors of phosphodiesterase type 5 (sildenafil), HMG-CoA reductase (simvastatin), calcium channel blockers – dihydropyridine derivatives (amlodipine, lacidipine), digoxin and warfarin. Displaying, that ivabradine has no clinically pronounced effect on the pharmacokinetics of simvastatin, amlodipina, lacidipine, digoxin pharmacokinetics and pharmacodynamics, warfarin and on the pharmacodynamics of acetylsalicylic acid.
In the pilot phase III trial use of the following drugs had no special restrictions, in connection with which they can be administered in combination with ivabradine with no special precautions: ACE inhibitors, angiotensin II receptor antagonists, Diuretic, nitrates short and prolonged action, HMG-CoA reductase, fibrates, proton pump inhibitors, oral hypoglycemics, acetylsalicylic acid and other antithrombotics.
Conditions of supply of pharmacies
The preparation is available on medical prescription.
Conditions and terms
The drug should be stored out of reach of children. No special storage conditions requires. Shelf life – 3 year. Do not use after expiration date, on the package.
