Implicor® (Implicor®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIvabradine + MetoprololIvabradine + Metoprolol
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  • Implicor®
    pills inwards 
    Servier Laboratories     France
    • Dosage form: & nbspfilm coated tablets
    Composition:

    Dosage of 5 mg + 25 mg: one tablet, film-coated, contains:

    active ingredients: ivabradine hydrochloride 5.39 mg (corresponding to 5 mg ivabradine base) and metoprolol tartrate 25 mg;

    Excipients: cellulose microcrystalline 71.37 mg, starch pregelatinized (corn) 48 mg, maltodextrin 8 mg, magnesium stearate 1.6 mg, silicon dioxide colloidal anhydrous 0.64 mg;

    Sheath: glycerol 0.241920 mg, hypromellose 4.021248 mg, macrogol 6000 0.256768 mg, magnesium stearate 0.241920 mg, titanium dioxide 0.774144 mg.

    Dosage 7.5 mg + 25 mg: one tablet, film-coated, contains:

    active ingredients: ivabradine hydrochloride 8.085 mg (corresponding to 7.5 mg ivabradine base) and metoprolol tartrate 25 mg;

    Excipients: cellulose microcrystalline 68.675 mg, starch pregelatinized (corn) 48 mg, maltodextrin 8 mg, magnesium stearate 1.6 mg, silicon dioxide colloidal anhydrous 0.64 mg;

    Sheath: glycerol 0.241920 mg, hypromellose 4.021248 mg, macrogol 6000 0.256768 mg, magnesium stearate 0.241920 mg, titanium dioxide 0.774144 mg.

    Dosage of 5 mg + 50 mg: one tablet, film-coated, contains:

    active ingredients: ivabradine hydrochloride 5.39 mg (corresponding to 5 mg ivabradine base) and metoprolol tartrate 50 mg;

    Excipients: cellulose microcrystalline 97.25 mg, starch pregelatinized (corn) 72 mg, maltodextrin 12 mg, magnesium stearate 2.4 mg, silicon dioxide colloidal anhydrous 0.96 mg;

    Sheath: glycerol 0.36288 mg, hypromellose 6.031872 mg, macrogol 6000 0.385152 mg, magnesium stearate 0.36288 mg, titanium dioxide 1.161216 mg.

    Dosage 7.5 mg + 50 mg: one tablet, film-coated, contains:

    active ingredients: ivabradine hydrochloride 8.085 mg (corresponding to 7.5 mg ivabradine base) and metoprolol tartrate 50 mg;

    Excipients: cellulose microcrystalline 94.555 mg, starch pregelatinized (corn) 72 mg, maltodextrin 12 mg, magnesium stearate 2.4 mg, silicon dioxide colloidal anhydrous 0.96 mg;

    Sheath: glycerol 0.36288 mg, hypromellose 6.031872 mg, macrogol 6000 0.385152 mg, magnesium stearate 0.36288 mg, titanium dioxide 1.161216 mg.

    Description:

    Tablets 5 mg + 25 mg

    Round, biconvex tablets, film-coated, white, with engraving on one side - , on the other - figure 1.

    Tablets 7.5 mg + 25 mg

    Oblong, biconvex tablets, film-coated, white, with engraving on one side - , on the other - figure 3.

    Tablets 5 mg + 50 mg

    Round, biconcave film coated tablets, white, with engraving on one side - on the other - number 2.

    Tablets 7.5 mg + 50 mg

    Oblong, biconvex tablets, covered with a film shell, white, with engravings on one side - , on the other - the figure 4.

    Pharmacotherapeutic group:Beta-blockers, other combinations
    ATX: & nbsp
  • Metoprolol in combination with ivabradine
    • Pharmacodynamics:

    Mechanism of action

    Iwabradine

    Ivabradine is a medication that slows the heart rhythm, the mechanism of its action is the selective and specific inhibition of the / g canals of the sinus node that control spontaneous diastolic depolarization in the sinus node and regulate the heart rate (HR). Iwabradine has a selective effect on the sinus node, without affecting the timing of impulses for atrial, atrioventricular and intragastric conducting paths, as well as contractility of the myocardium and repolarization of the ventricles. Iwabradine can also interact with Ih canals of the retina of the eye, similar to If channels of the heart. They participate in the emergence of a temporary change in the system of visual perception due to a change in the reaction of the retina to bright light stimuli. Under provocative circumstances (for example, rapid change of brightness in the field of the visual field) partial inhibition Ih channels with ivabradine causes a phenomenon of change in light perception (phosphene). Phosphenes are characterized by transient intensification of brightness in a limited area of ​​the visual field (see section "Side effect").

    Metoprolol

    Metoprolol is a cardioselective blocker that blocks β1-adrenoceptors (located predominantly in the heart) at doses significantly lower than the doses required to block β2-adrenoreceptors (localized mainly in the peripheral vessels and bronchi). Metoprolol does not have membrane-stabilizing and internal sympathomimetic activity (ICA).

    Pharmacodynamic properties

    Iwabradine

    The main pharmacological feature of ivabradine is the ability of a dose-dependent reduction in the heart rate (heart rate).Analysis of the dependence of the decrease in heart rate on the dose of the drug was carried out with a gradual increase in the dose of ivabradine up to 20 mg twice a day and revealed a tendency to achieve the "plateau" effect, which reduces the risk of pronounced bradycardia (heart rate less than 40 beats per minute) (See " Side effect").

    When prescribing the drug at recommended doses, the degree of decrease in heart rate is approximately 10 beats / minute at rest and under physical exertion. As a result, the work of the heart decreases and myocardial oxygen demand decreases.

    Ivabradin does not affect intracardiac conduction, contractility of the myocardium (does not have a negative inotropic effect) and the process of repolarization of the ventricles of the heart. In clinical electrophysiological studies ivabradine had no influence on the time of impulses on the atrioventricular or intraventricular conduction pathways, as well as on the adjusted intervals QT.

    In patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%), it was shown that ivabradine did not affect LVEF.

    Metoprolol

    Metoprolol reduces or blocks the effect of catecholamines on the heart, which leads to a decrease in heart rate, myocardial contractility and cardiac output.It has an antihypertensive effect both in the standing and lying position, and also prevents the lifting of blood pressure during physical exertion.

    Clinical efficacy and safety

    Iwabradine

    Antibiotic and antiischemic efficacy of ivabradine was studied in 5 studies (three of which were compared with placebo and one each compared to atenolol and amlodipine) in patients with stable chronic angina.

    Determined that ivabradine in a dose of 5 mg 2 times a day, improved the performance of stress tests after 3-4 weeks of therapy. Efficiency was confirmed for a dose of 7.5 mg twice a day. In particular, an additional effect with increasing the dose from 5 to 7.5 mg twice a day was established in a comparative study with atenolol. lead time physical activity increased by approximately 1 minute after 1 month of ivabradine administration at a dose of 5 mg twice a day, while after an additional 3-month course of ivabradine 7.5 mg twice daily, a further increase in this indicator was noted for 25 seconds. Antianginal and antiischemic 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 twice a day was noted for all parameters of stress tests (total duration of exercise, time to the limiting angina attack, time before the onset of angina attack, and time to development of the segment depression ST at 1 mm), and also was accompanied by a decrease in the incidence of angina attacks by about 70%. The use of ivabradine 2 times a day provided a constant therapeutic effectiveness within 24 hours.

    Reception of ivabradin by patients receiving atenolol in a dose of 50 mg once a day, showed additional efficacy against all parameters of stress tests at a drop in its pharmacological activity (12 hours after ingestion).

    Ivabradin on the decline of pharmacological activity (12 hours after ingestion) had no additional effect when added to amlodipine at a dose of 10 mg per day, while at the maximum activity ivabradine (3-4 hours after ingestion), its additional efficacy was demonstrated.

    Ivabradin on the decline of pharmacological activity (after 12 hoursafter ingestion) for a 6-week treatment showed statistically significant additional efficacy in achieving a response to treatment (defined as a reduction in angina attacks, at least up to 3 per week and / or an increase in time to development of segment depression ST by 1 mm for at least 60 seconds during the stress test on the treadmill) when added to amlodipine at a dose of 5 mg once daily or to nifedipine at a dose of 30 mg once daily. There was no improvement in the efficacy of ivabradine, evaluated by achieving secondary endpoints when performing stress tests, on the decline of therapeutic activity, while efficacy was shown at the maximum activity (3-4 hours after ingestion of ivabradine).

    In studies of the clinical efficacy of the drug, ivabradine effects were completely preserved during 3 and 4-month periods of treatment. During There were no signs of development of tolerance (decrease in efficacy), and after the cessation of treatment of the "withdrawal" syndrome was not noted. Antianginal and antiischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as a significant decrease in the work product (heart rate x systolic blood pressure), both at rest and during physical exertion. The effect on blood pressure (BP) and overall peripheral vascular resistance) was insignificant and clinically insignificant.

    A steady decrease in heart rate was noted in patients receiving ivabradine for at least 1 year. Influences on carbohydrate metabolism and lipid profile were not observed.

    In patients with diabetes mellitus, 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 more than 40%) on the background of maintenance therapy, ivabradine therapy at doses higher than recommended (initial dose of 7.5 mg twice daily (5 mg twice daily, 75 years), which was then titrated to 10 mg twice daily) did not significantly affect the primary combined endpoint (death due to cardiovascular causes or the development of non-fatal myocardial infarction). The incidence of bradycardia in the group of patients who received ivabradine, was 17.9%, in the placebo group - 2.1%. 7.1% of patients in the study took verapamil, diltiazem or potent inhibitors of the isoenzyme CYP3A4.

    In patients with angina class II or higher, according to the classification of the Canadian Cardiological Society, a small statistically significant increase in the incidence of the primary combined endpoint with ivabradine was observed, which was not observed in the subgroup of all patients with angina (grade 1 and higher). In this study, a higher dose was used than in the approved dose, which nevertheless does not explain the results obtained.

    In a study involving patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-blockers, there was no difference between the groups of patients taking ivabradine on the background of standard therapy, and placebo, according to the total frequency of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or symptoms of chronic heart failure (CHF).Patients with symptomatic angina did not show significant differences in the incidence of death due to a cardiovascular cause or hospitalization due to the development of non-fatal myocardial infarction or heart failure (incidence of 12.0% in the ivabradine group and 15.5% in the placebo group, respectively ).

    Metoprolol

    Patients with ischemic heart disease metoprolol reduces the frequency and severity of episodes of ischemia and increases tolerance to physical exertion. These positive effects of metoprolol may be due to a decrease in myocardial oxygen demand as a result of a decrease in heart rate and myocardial contractility.

    Application the children and adolescents

    The use of Implicor® in children and adolescents under the age of 18 has not been adequately studied (see the section "Pharmacokinetics").

    Pharmacokinetics:

    The speed and extent of absorption of ivabradine and metoprolol when ingested in the Implicor® formulation are not significantly different from the corresponding rates of speed and degree of absorption in cases where both drugs are used separately.

    Iwabradine

    In physiological conditions ivabradine quickly released from the tablet and readily soluble in water (solubility more than 10 mg / ml). Iwabradine represents S- enantiomer. with the lack of bioconversion according to research data in vivo. The main active metabolite of the drug is N-desmethylated derivative of ivabradine.

    Absorption and bioavailability

    After ingestion ivabradine quickly and almost completely absorbed in the gastrointestinal tract. The maximum concentration in the blood plasma (CmOh) is achieved approximately 1 hour after ingestion on an empty stomach. Absolute bioavailability of film-coated tablets is approximately 40%, which is due to the effect of "first passage" through the intestine and liver.

    The intake increases the absorption time by approximately 1 hour and increases the exposure from 20% to 30%. To reduce the variability of exposure, the drug is recommended to be taken concomitantly with the intake of food (see section "Method of administration and dose").

    Distribution

    The connection with plasma proteins is approximately 70%. The volume of distribution in patients in an equilibrium state is about 100 liters. FROMmOh at long reception in a dose of 5 mg 2 once a day is 22 ng / ml (coefficient of variation, CV = 29%). The average equilibrium concentration in blood plasma is 10 ng / ml (CV=38%).

    Metabolism

    Ivabradine is largely metabolized in the liver and intestines by oxidation involving only the cytochrome P450 isoenzyme 3A4 (CYP3A4). The main active metabolite is N-desmethylated ivabradine derivative (S 18982), whose proportion is 40% of the administered dose of ivabradine. The metabolism of this active metabolite of ivabradine also occurs with the participation of the isoenzyme CYP3A4. Ivabradine has an insignificant affinity to the isoenzyme CYP3A4, does not induce and does not inhibit it and, as a result, does not affect the metabolism or concentration of isoenzyme substrates CYP3A4 in the blood plasma. On the contrary, the use of powerful inhibitors or inducers of isoenzyme CYP3A4, may be accompanied by a significant change in the concentration of ivabradine in the blood plasma (see section "Interaction with other drugs").

    Excretion

    The half-life period (T1 / 2) of ivabradine from plasma is an average of 2 hours (70-75% of the area under the concentration-time curve, AUC), and effective T1 / 2 - 11 hours.

    The total clearance is approximately 400 ml / min, the renal clearance is 70 ml / min. Excretion of metabolites occurs at the same rate through the kidneys and intestines. About 4% of the accepted dose is excreted by the kidneys unchanged.

    Linearity / Nonlinearity of Pharmacokinetics

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

    Special patient groups

    Elderly patients

    Pharmacokinetic parameters (AUC and Cmax) do not differ significantly in the groups of patients 65 years of age or older, 75 years and older, and in the general population of patients (see the section "Dosing and Administration").

    Impaired renal function

    The effect of decreased renal function (clearance of creatinine, CK, 15 to 60 ml / min) on the kinetics of ivabradine is minimal, since only about 20% of ivabradine and its active metabolite S 18982 is excreted by the kidneys (see section "Method of administration and dose").

    Impaired liver function

    In patients with mild liver failure (up to 7 on the Child-Pugh scale) AUC free ivabradine and its active metabolite is 20% greater than in patients with normal liver function. Data on the use of ivabradin in patients with moderate (7-9 points on the Child-Pugh scale) liver failure are limited and do not allow to draw a conclusion about the pharmacokinetics of the drug in this group of patients.Data on the use of ivabradin in patients with severe (10 points or more on the Child-Pugh scale) liver failure are currently not available (see the sections "Contraindications" and "Method of administration and dose").

    The relationship between pharmacokinetic and pharmacodynamic properties

    Analysis of the relationship between pharmacokinetic and pharmacodynamic properties allowed us to establish that the decrease in heart rate is in direct proportion to the increase in the concentration of ivabradine and its active metabolite S 18982 in blood plasma when taken in doses up to 15-20 mg 2 times a 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 the "plateau". High concentrations of ivabradine, which can be achieved with a combination of the drug with potent inhibitors of isoenzyme CYP3A4, can lead to a marked decrease in heart rate. When combined with moderate inhibitors of isoenzyme CYP3A4 this risk is lower (see the sections "Contraindications", "Interaction with other medicines" and "Special instructions").

    Metoprolol

    Suction and distribution

    After oral administration metoprolol completely absorbed from the gastrointestinal tract. FROMmOh in blood plasma is achieved after 1.5-2 hours after administration.

    Because of the "first pass" effect through the liver, bioavailability is approximately 50% with a single ingestion. Simultaneous food intake increases bioavailability by about 30-40%. Linkage to blood plasma proteins is insignificant (5-10%).

    Metabolism

    Metoprolol is metabolized in the liver by oxidation. With the known main metabolite, metoprolol does not have a significant beta-blocking activity.

    In the metabolism of the drug, the main, but not the only, part is isoenzyme CYP2D6. Due to polymorphism of the isoenzyme gene CYP2D6, the metabolic rate of metoprolol in patients exhibits interindividual variability. In patients with a low metabolic rate (7-8%), a higher concentration of metoprolol in the blood plasma and a slower elimination of it are compared with patients with a high metabolic rate.

    Excretion

    Concentration after ingestion in the blood plasma is constant and reproducible individually in patients, however, more than 95 % metoprolol and its metabolites is excreted through the kidneys, in an unchanged form - about 5%, in some cases - up to 30%. The half-life (T]/0) is about 3.5 hours (from 1 to 9 hours). Plasma clearance is about 1 L / min.

    Special patient groups

    Elderly patients

    Pharmacokinetic parameters (AUC and CmOh) are not significantly different in elderly patients (65 years and older) and younger.

    Impaired liver function

    The bioavailability of metoprolol increases and the rate of its excretion decreases.

    Application in pregnancy and during breastfeeding

    Metoprolol penetrates the placental barrier. The average ratio of metoprolol in the umbilical cord and the mother's blood is 1.

    Metoprolol penetrates into breast milk. The concentration of metoprolol in breast milk may be 3.7 times higher than its concentration in the mother's blood.

    Indications:

    Symptomatic treatment of stable angina pectoris in adult patients with normal sinus rhythm, the condition of which was adequately controlled by the use of a combination of ivabradine and metoprolol monotherapy in the same doses.

    Contraindications:

    - Hypersensitivity to ivabradine, metoprolol (and other drugs of the group of beta-blockers due to possible cross-sensitivity), as well as to the auxiliary substances that make up the drug;

    - Severe or symptomatic bradycardia (see section "Method of administration and dose");

    - Cardiogenic shock;

    - Acute myocardial infarction or suspected acute myocardial infarction complicated by severe bradycardia, grade I atrioventricular block, arterial hypotension (systolic blood pressure (BP) less than 100 mmHg) and / or severe heart failure;

    - Syndrome of weakness of the sinus node (including, sinoatrial blockade);

    - Atrioventricular blockade of II and III degree;

    - Severe arterial hypotension (BP less than 90/50 mm Hg) or symptomatic arterial hypotension;

    - Unstable or acute heart failure;

    - Patients receiving intermittent short-term treatment with beta-adrenomimetics;

    - Patients who are dependent on a pacemaker (in whom the heart rhythm is provided only by constant pacemaking);

    - Unstable angina;

    - Severe peripheral vascular disease;

    - Untreated pheochromocytoma;

    - Severe hepatic impairment

    - Metabolic acidosis;

    - Simultaneous application with powerful inhibitors of isoenzymes CYP3A4, such as antifungal agents of the azole group (ketoconazole, itraconazole), antibiotics of the macrolide group (clarithromycin, erythromycin for oral administration, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see sections "Pharmacokinetics" and "Interaction with other medicinal products").

    - Simultaneous use with verapamil or diltiazem, as they refer to moderate inhibitors of isoenzyme CYP3A4 and have the ability to reduce heart rate (see section "Interaction with other drugs").

    - Pregnancy, breastfeeding and use by women with preserved childbearing potential, not using reliable methods of contraception (see section "Application during pregnancy and during breast-feeding");

    - Age under 18 years (efficacy and safety of use in this age group has not been studied).

    Carefully:

    Have patients with:

    moderately expressed hepatic insufficiency (less than 9 on the Child-Pugh scale); arterial hypotension of mild and moderate severity; congenital lengthening the interval QT or concomitantly taking medication, lengthening the interval QT; angina of Prinzmetal; bronchial asthma or chronic obstructive pulmonary disease; atrioventricular blockade of 1 degree; with heart rhythm disturbances; stroke; severe renal dysfunction (creatinine clearance less than 15 mL / min); arterial hypertension; chronic heart failure; obstructive pulmonary disease; diabetes mellitus, especially with the simultaneous use of insulin or oral hypoglycemic drugs; psoriasis; thyrotoxicosis; pigmented degeneration of the retina; severe history of hypersensitivity reactions and those receiving desensitizing therapy, the elderly (over 65 years of age) (see section "Special instructions").

    When: CHF and violations of intraventricular conduction (blockage of the left or right leg of the bundle of His) and ventricular dissynchrony; CHF IV functional class by classification NYHA (New York Heart Association); simultaneous use of amiodarone or powerful antiarrhythmic drugs of the 1st class; general anesthesia (see section "Special instructions").

    Warnings regarding simultaneous admission with other medicinal products are indicated in the section "Interaction with other medicinal products".

    Pregnancy and lactation:

    Pregnancy

    The drug Implicor® is contraindicated in pregnancy, given the available data for its components (see the section "Contraindications"),

    At the moment, there is insufficient data on the use of ivabradine during pregnancy. In animal studies, reproductive toxicity was demonstrated, embryotoxic and teratogenic effects of ivabradine were identified. Potential risk in humans is not established, so the use of ivabradine during pregnancy is contraindicated.

    Data on the use of metoprolol during pregnancy are limited (less than 300 cases of completed pregnancies are known). The results of animal studies do not demonstrate direct or indirect reproductive toxicity of metoprolol. Metoprolol it is possible to prescribe to pregnant women only in case of emergency. Beta-blockers reduce blood flow through the placenta, which can increase the risk of premature birth, miscarriage and intrauterine fetal death. It is also possible the appearance of a number of undesirable effects in the fetus and the newborn, including hypoglycemia, bradycardia, lowering blood pressure and breathing disorders. The risk of cardiopulmonary complications is higher in the postnatal period. The use of the drug during pregnancy should be accompanied by constant monitoring of the fetus, as well as within a few days after childbirth.

    Breastfeeding period

    The use of the drug Implicor® during breastfeeding is contraindicated (see the section "Contraindications"). In animal studies, it was found that ivabradine excreted in breast milk. If it is necessary to use ivabradine, breastfeeding should be discontinued and another way of feeding the baby should be selected. Metoprolol accumulates in breast milk in an amount 3 times the concentration in the blood plasma of the mother.

    Fertility

    Clinical evidence of the effect of Implicor® on fertility is not available.

    In preclinical studies, the effect of ivabradine and metoprolol on the fertility of animals has not been established.

    Women with preserved reproductive potential

    Women with preserved reproductive potential should use reliable contraceptive methods while taking the drug (see section "Contraindications").

    Dosing and Administration:

    Implicor® should be taken orally 1 tablet 2 times a day, in the morning and in the evening, while eating, with a sufficient amount of liquid. The concentration of metoprolol in the blood plasma increases with simultaneous intake with food (see section "Pharmacokinetics"). This fact should be taken into account in the treatment of patients who took metoprolol on an empty stomach before prescribing the Implicor® drug.

    The drug Implicor® is prescribed only to patients who are already taking ivabradine and metoprolol in optimal doses.

    If necessary, dose adjustment should be performed with mono preparations of ivabradine and metoprolol.

    The decision to change the dosage regimen is recommended on the basis of a number of examinations, including heart rate, ECG or 24-hour Holter monitoring,and also under condition of stable reception by the patient of an optimum dose of metoprolol and ivabradine.

    If there is no decrease in symptoms of angina within 3 months after the start of treatment, Implicom® treatment should be discontinued.

    If, during the period of treatment, the heart rate at rest drops below 50 beats / min or the patient develops symptoms typical of bradycardia (dizziness, fatigue or lowering blood pressure), the dose of the drug should be reduced by selecting a new dose for preparations based on mono-components to ensure the optimal dose of metoprolol. After reducing the dose of mono-components ivabradine and metoprolol, it is necessary to control heart rate (see section "Special instructions"). Treatment should be canceled if, despite a reduction in dose, the heart rate remains below 50 bpm, or the symptoms of bradycardia persist.

    With renal insufficiency

    Patients with renal failure with a creatinine clearance above 15 ml / min do not need to change the dose of Implicor®.

    With a decrease in creatinine clearance below 15 ml / min, use the drug with caution.

    With hepatic insufficiency

    Implicor® can be used in patients with mild hepatic insufficiency.

    Caution should be exercised when using Implicor® in patients with moderate hepatic impairment.

    Patients with hepatic insufficiency of severe severity of the drug is contraindicated (see section "Pharmacokinetics" and "Contraindications").

    Elderly patients

    In patients over 65 years of age, Implicor® should be used with caution (see "With caution").

    Application in children and adolescents

    The efficacy and safety of the Implicor® drug in children and adolescents under 18 years of age has not been established (no data).

    Side effects:

    The safety profile of Implicor® is based on the known safety profiles of each of its active ingredients individually.

    Of undesirable drug reactions (NLR) against the background of ivabradine, the most frequently observed: changes in light perception (phosphenes) and bradycardia. These NLRs were dose-dependent and related to the mechanism of action of the drug.

    The most frequent NLPs during treatment with metoprolol were: bradycardia, nightmarish dreams, headache, drowsiness, insomnia, dizziness, palpitations, orthostatic hypotension, cold extremities, Raynaud's disease, dyspnoea with exertion, nausea, constipation, diarrhea, abdominal pain , vomiting, fatigue, violation of libido.

    Table 1 provides information on NLR, which were noted with the use of ivabradine and metoprolol separately, and classified according to MedDRA. The following classification is used to designate the frequency:

    Often: ≥ 1/10

    Often: from ≥ 1/100 to <1/10

    Infrequently: from ≥ 1/1000 to <1/100

    Rarely: from ≥ 1/10000 to <1/1000

    Very rarely <1/10000

    The frequency is not specified (can not be determined from available data).

    Table 1. Undesirable reactions observed with the use of ivabradine and metoprolol

    Organ organs and systems (MedDRA terminology)

    Unwanted reaction (in terminology MedDRA)

    Frequency

    Iwabradine

    Metoprolol

    Violations of the blood and lymphatic system

    eosinophilia

    infrequently

    thrombocytopenia

    rarely

    leukopenia

    rarely

    Immune system disorders

    exacerbation of psoriasis

    infrequently

    Disorders from the metabolism and nutrition

    hyperuricemia

    infrequently

    hypoglycemia

    infrequently

    Disorders of the psyche

    depression

    infrequently

    nightmares, pathological dreams

    often

    increased excitability

    rarely

    anxiety

    rarely

    confusion

    infrequently

    hallucinations

    infrequently

    depersonalization

    rarely

    Disturbances from the nervous system

    headache

    often

    often

    amnesia

    rarely

    slowing the speed of mental and motor reactions, understanding

    infrequently

    drowsiness

    often

    insomnia

    often

    dizziness

    often

    often

    episodes of loss of consciousness

    infrequently*

    rarely

    paresthesia

    infrequently

    stupor

    infrequently

    Disturbances on the part of the organ of sight

    Changes in light perception (phosphenes)

    Often

    blurred vision

    often

    blurred vision

    infrequently*

    rarely

    xerophthalmia

    rarely

    dry eye syndrome

    infrequently

    conjunctival eye irritation

    infrequently

    decrease in production of tears

    rarely

    diplopia

    infrequently*

    conjunctivitis

    rarely

    Hearing disorders and labyrinthine disorders

    systemic dizziness (vertigo)

    infrequently

    noise in ears

    rarely

    hearing loss, hearing loss

    rarely

    deafness

    rarely

    Heart Disease

    bradycardia

    often

    often

    atrioventricular block of 1 degree (on the ECG extension of the interval PQ)

    often

    atrioventricular block of degree I

    infrequently

    ventricular extrasystoles

    often

    heart palpitations

    infrequently

    often
    supraventricular extrasystoles

    infrequently

    atrial fibrillation

    often

    atrioventricular block of degree II

    rarely

    atrioventricular blockade of degree III

    rarely

    syndrome of weakness of the sinus node

    rarely

    heart failure

    infrequently

    cardiogenic shock

    infrequently

    Increase and aggravation of seizures in patients with angina

    rarely

    heart rhythm disturbances

    rarely

    conduction disturbance of the myocardium

    rarely

    chest pain

    infrequently

    uncontrolled blood pressure

    often

    arterial hypotension (possibly due to bradycardia)

    infrequently*

    orthostatic hypotension (with syncope)

    often

    chill sensation

    often

    Raynaud's disease

    often

    dry gangrene (in patients with severe vascular disorders of the limbs before treatment)

    rarely

    intermittent claudication

    infrequently

    BP reduction

    infrequently

    Disturbances from the respiratory system, chest and mediastinal organs

    dyspnea

    infrequently

    bronchospasm (including patients who have no history of bronchial obstructive syndrome)

    infrequently

    rhinitis

    rarely

    dyspnoea with physical exertion

    often

    Disorders from the gastrointestinal tract

    nausea

    infrequently

    often

    constipation

    infrequently

    often

    diarrhea

    infrequently

    often

    stomach ache

    infrequently*

    often

    vomiting

    often

    dryness of the oral mucosa

    rarely

    dysgeusia

    rarely
    retroperitoneal fibrosis

    rarely

    Disturbances from the liver and bile ducts

    hepatitis

    rarely

    deviations in liver function

    rarely

    liver dysfunction

    rarely

    Disturbances from the skin and subcutaneous tissues

    angioedema

    infrequently*

    skin rash

    infrequently*

    infrequently

    dystrophic skin changes

    infrequently

    redness of the skin

    rarely*

    itchy skin

    rarely*

    hives

    rarely*

    infrequently

    hyperhidrosis

    infrequently

    alopecia

    rarely

    Photosensitivity reactions

    rarely
    psoriasis, skin psoriasis-like rashes

    infrequently

    Disturbances from musculoskeletal and connective tissue

    muscle spasms

    infrequently

    rarely

    arthralgia

    rarely

    muscle weakness

    rarely

    muscle cramps

    infrequently

    asthenia (possibly as a consequence of bradycardia)

    infrequently*

    General disorders and disorders at the site of administration

    increased fatigue

    infrequently*

    Often

    general malaise (possibly as a consequence of bradycardia)

    rarely*

    edema

    infrequently

    weight gain

    infrequently

    Laboratory and instrumental data

    increase in creatinine in blood plasma

    infrequently

    interval lengthening QT on the ECG

    infrequently

    increased activity of "liver" transaminases

    rarely

    Disorders from the reproductive system and mammary glands

    		 sexual dysfunction / impotence

    rarely

    violation of libido

    often

    Peyronie's disease

    rarely

    * The incidence of side effects for spontaneous reports is calculated from clinical research

    Individual undesirable reactions

    Change in light acceptance (Phosphenes) It was noted in 14.5% of patients and was described as a transient change in brightness in a limited area of ​​the visual field. As a rule, similar phenomena were provoked by a sharp change in the intensity of illumination. Phosphenes can also appear, which have the appearance of areola, the decay of the visual image into separate parts (stroboscopic and kaleidoscopic effects), manifested as bright color flashes or multiple images (persistence of the retina).Typically, the symptoms appear within the first 2 months of treatment and are then repeated. The expression of phosphenes is usually weak or moderate. All symptoms ceased during or after treatment, and 77.5% of patients disappeared during treatment. Less than 1% of patients were forced to change the regime of the day or stop treatment with the drug due to the occurrence of their phosphenes.

    Bradycardia was observed in 3.3% of patients, mainly during the first 2-3 months of treatment. In 0.5% of patients marked bradycardia with a heart rate of 40 beats / min and less.

    According to the clinical study atrial fibrillation was observed in 5.3% of patients taking ivabradine, compared with 3.8% in the placebo group. According to the analysis of the combined data of clinical studies with a follow-up period of at least 3 months, involving more than 40,000 patients, atrial fibrillation was observed in 4.86% of patients receiving ivabradine, in comparison with 4,08% in control groups.

    Overdose:

    No cases of drug overdose Implicor® have been reported.

    Symptoms of overdose:

    Related to ivabradine symptoms of an overdose may include a pronounced and prolonged bradycardia.

    Associated with metoprolol. A marked decrease in blood pressure, sinus bradycardia, atrioventricular blockade, heart failure, cardiogenic shock, cardiac arrest, bronchoconstriction, confused consciousness, coma, nausea, vomiting, cyanosis of the skin and mucous membranes can be observed. Symptoms can increase with the simultaneous use of alcohol, the use of antihypertensive drugs, quinidine containing medicines, as well as barbiturates.

    Symptoms of overdose can appear after 20 minutes (up to 2 hours) after taking the drug.

    Treatment

    In addition to general measures (gastric lavage, which is carried out within 4 hours after taking the drug and in case of severe intoxication, and taking activated carbon), patients should be monitored in the intensive care unit where vital signs are corrected, if necessary.

    In the case of severe bradycardia symptomatic therapy is indicated. With a bradycardia with a violation of hemodynamics, intravenous β-adrenomimetics, for example isoprenaline, are administered.If necessary, temporary artificial pacemaker can be implanted. The potential antiparticle of metoprolol is atropine (in a dose of 0.5-2 mg intravenously), its introduction is preceded by intravenous administration of glucagon (1-5 mg, but not more than 10 mg). Additionally, it is possible to administer sympathomimetics in doses calculated on the patient's body weight and taking into account the desired clinical effect (dobutamineadrenaline). Doses exceeding the therapeutic dose may be required.

    With cramps, slow intravenous diazepam is recommended.

    Interaction:

    In studies on the interaction between ivabradine and metoprolol in healthy volunteers, there is no mutual effect on the effects of each of the active substances. Below you will find information on possible interactions with other medicinal products.

    Contraindications for simultaneous use

    Related to ivabradine

    Simultaneous use of ivabradine with potent inhibitors of isoenzyme CYP3A4, such as antifungal agents of the azole group (ketoconazole, itraconazole), antibiotics of the macrolide group (clarithromycin, erythromycin for oral administration, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, is contraindicated (see section "Contraindications"). Powerful inhibitors of isoenzyme CYP3A4 - ketoconazole (200 mg once a day) or josamycin (1 g 2 times a day) increase the average concentration of ivabradine in blood plasma by 7-8 times.

    Metoprolol associated

    Simultaneous short-term treatment with beta-adrenomimetics with metoprolol is contraindicated (see section "Contraindications").

    Associated with ivabradine and metoprolol

    Moderate inhibitors of isoenzyme CYP3A4: the combined use of ivabradine and diltiazem or verapamil (heart rhythm-reducing agents) in healthy volunteers and patients was accompanied by an increase AUC ivabradine 2-3 times and an additional decrease in heart rate by 5 beats / min. This combination of drugs is contraindicated (see section "Contraindications").

    Blocks of "slow" calcium channels (BCCI), such as verapamil or diltiazem, with intravenous administration may increase the antihypertensive effect of beta-blockers, exacerbating the effect on heart rate, atrioventricular conduction and contractility of the myocardium. Possible intensification of negative inotropic and chronotropic effects.In this regard, during the treatment with beta-blockers intravenous injection of BCCM, it is contraindicated (see the section "Contraindications").

    Undesirable combinations of drugs

    Related to ivabradine

    - Medicinal products, extension intervals QT

    - Antiarrhythmic drugs that extend the interval QT (eg, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone)

    - Drugs that extend the interval QT, not related to antiarrhythmic agents (eg, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for intravenous administration).

    Avoid simultaneous use of ivabradine and these drugs, because a decrease in heart rate may cause an additional lengthening of the interval QT. If you need to co-prescribe these drugs, you should carefully monitor the ECG parameters (see section "Special instructions").

    - Grapefruit juice: on the background of taking grapefruit juice, there was an increase in the concentration of ivabradine in the blood 2 times. When the drug is treated, grapefruit juice should be avoided whenever possible.

    Metoprolol associated

    The following combinations with metoprolol should be avoided:

    Barbiturates: with the simultaneous use of phenobarbital it is proved that Barbiturates significantly increase the metabolism of metoprolol due to induction of the enzyme. Decreased plasma concentrations of metoprolol and, as a consequence, a decrease in its therapeutic effect (a more active hepatic metabolism) was noted against the background of the use of phenobarbital.

    Hypotensive means of central action (eg, clonidine)

    A significant increase in blood pressure is possible with sudden withdrawal of drugs of central action. Do not abruptly stop taking antihypertensive drugs of central action. Sudden abolition of such drugs, especially if it preceded the abolition of the beta-blocker, may increase the risk of "withdrawal syndrome".

    Simultaneous administration of clonidine and nonselective beta-blockers, and possibly selective beta-blockers, increase the risk of "withdrawal syndrome". In the case of simultaneous reception of clonidine, its reception should be continued for some time in case of cancellation of the beta-blocker.

    Antiarrhythmic drugs I class (eg, quinidine, tokainide, procainamide, Aymalin. amiodarone, flecainide and disopyramide).

    Beta-blockers can enhance the negative inotropic effect of antiarrhythmic drugs and increase the time of intrapartum conduction. In patients with dysfunction of the sinus node, simultaneous administration with amiodarone may be accompanied by an increase in electrophysiological effects, with the development of bradycardia, blockade of the sinus node and atrioventricular blockade. The half-life period of amiodarone is very long (about 50 days), therefore after its cancellation the interaction of drugs can appear clinically after a long period of time. Antiarrhythmic drugs I class, such as quinidine, tokainide, procainamide, Aymalin, amiodarone, flecainide and disopyramid, potentiate the effect of metoprolol on heart rate and atrioventricular conductivity.

    Accompanying use with caution

    Associated with ivabradine

    - Non-potassium-sparing diuretics (thiazide and loop diuretics): hypokalemia may increase the risk of arrhythmias. Due to ivabradine it can cause a bradycardia,the combination of hypokalemia and bradycardia can predispose to the development of severe cardiac rhythm disturbances, especially in patients with the syndrome of an elongated interval QT, regardless of whether the lengthening interval QT congenital or due to the effects of medications.

    - Moderate inhibitors of isoenzyme CYP3A4: the use of ivabradine in combination with other mild isoenzyme inhibitors CYP3A4 (for example, fluconazole) is possible with the appointment of minimum doses of ivabradine, 2.5 mg twice a day, those patients whose heart rate at rest is more than 70 beats / min, under the control of heart rate.

    - Inductors of isoenzyme CYP3A4: (for example, such as rifampicin. barbiturates, phenytoin and St. John's wort perforated) with joint application may lead to a decrease in blood concentrations and activity of ivabradine and require an increase in dose ivabradine. With the combined use of ivabradine 10 mg 2 times a day and preparations containing St. John's Wort, a two-fold decrease AUC ivabradine. Do not use drugs containing St. John's wort perforated, against the background of ivabradine therapy.

    Metoprolol associated

    Metoprolol is a substrate of isoenzyme CYP2D6 cytochrome P450. Substances that induce and inhibit enzymes can alter the concentration of metoprolol in the blood plasma.

    - Rifampicin reduces the concentration of metoprolol in the blood plasma.

    - Cimetidine, preparations, containing ethanol, hydralazine can increase the concentration of metoprolol in the blood plasma. Metoprolol is metabolized primarily in the liver, but not only, with the participation of isoenzyme CYP2D6 (see section "Pharmacokinetics").

    - isozyme inhibitory drugs CYP2D6, for example, selective serotonin reuptake inhibitors, such as paroxetine. fluoxetine and sertraline, and diphenhydramine. hydroxychloroquine, celecoxib, terbinafine, drugs of a group of neuroleptics (for example, chlorpromazine, triflupromazine, chloroprotoxen) and, perhaps, propafenone, can increase the concentration of metoprolol in the blood plasma.

    - Inhibitory effect of isoenzyme CYP2D6 also noted in amiodarone and quinidine (antiarrhythmic drugs).

    Metoprolol may reduce the excretion of other drugs (eg, lidocaine).

    In patients taking beta-adrenoblockers, inhalation anesthetics increase bradycardia.

    It may be necessary to reduce the dose of metoprolol in the case of starting drugs in the following groups:

    - Nitrates - in connection with the risk of increasing the hypotensive effect of metoprolol;

    - Cardiac glycosides (digoxin) - with simultaneous admission with beta-blockers may slow the rate of atrioventricular conduction and cause bradycardia;

    - Beta-blockers (eg eye drops) and monoamine oxidase (MAO) inhibitors - it is recommended to carefully monitor the condition of patients, since with simultaneous admission with beta-blockers increases the risk of bradycardia and increased hypotensive effect.

    - Adrenalin: if, under certain circumstances, patients receiving runabrainage blockers need adrenaline injection, it must be taken into account that the hypotensive effect is much less pronounced in cardioselective beta-blockers than in nonselective ones.

    - Parasympathomimetics: simultaneous reception of parasympatomimetics can cause a prolonged bradycardia.

    - Non-steroidal anti-inflammatory drugs (NSAIDs): simultaneous administration of NSAIDs, for example, indomethacin. can reduce the antihypertensive effect of metoprolol.

    - Insulin and oral hypoglycemic drugs

    Metoprolol may increase the hypoglycemic effect of oral hypoglycemic drugs and lead to masking of symptoms of hypoglycemia. You may need to change the dose of oral hypoglycemic drugs.

    Combinations of medicines that need to be taken into account:

    Related to ivabradine

    The absence of a clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradin was shown with simultaneous use of the following drugs: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, inhibitors of HMG-CoA reductase (simvastatin), dihydropyridine derivatives of BCCC (amlodipine, lacidipine), digoxin and warfarin. Shown, that ivabradine has no clinically significant effect on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacodynamics and pharmacokinetics of digoxin, warfarin, and on the pharmacodynamics of acetylsalicylic acid.

    In clinical trials, there was no change in the safety profile when appliedivabradine with: angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, beta-adrenoblockers, diuretics, aldosterone antagonists, short-acting and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, hypoglycemic agents for oral ingestion, acetylsalicylic acid and other antiplatelet agents.

    Cytochrome P4503A4 (isoenzyme CYP3A4): ivabradine is metabolized in the liver with the participation of isoenzyme CYP3A4 and is a very weak inhibitor of this cytochrome. Iwabradine does not have a significant effect on the metabolism and concentration in the blood plasma of other substrates (potent, moderate and weak inhibitors) of the isoenzyme CYP3A4. At the same time, inhibitors and inducers of isoenzyme CYP3A4 can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It was found that inhibitors of isoenzyme CYP3A4 increase, and isoenzyme inducers CYP3A4 reduce the concentration of ivabradine in blood plasma. Increasing the concentration of ivabradine in blood plasma may increase the risk of developing severe bradycardia (see section "Special instructions").

    Metoprolol associated

    - Simultaneous reception tricyclic antidepressants and antipsychotics may be accompanied by increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

    - Simultaneous application mefloquine may be accompanied by a risk of developing severe bradycardia (additive effect).

    - At simultaneous intravenous administration of dipyridamole possibly increased antihypertensive effect.

    - Alfa-adrenoblockers, used in urology (alfuzozin, doxazosin, prazozin, tramzulosin, terazosin), may increase the hypotensive effect of metoprolol and increase the risk of orthostatic hypotension.

    - Ergotamine (with joint admission - possibly increased vasoconstriction).

    - Curare like muscle relaxants (strengthening neuromuscular blockade).

    - Floktaphenin (beta-blockers may interfere with the compensatory response from the cardiovascular system associated with arterial hypotension or shock, which can develop against floktaphenin).

    - Antacids - while concomitant reception showed an increase in the concentration of metoprolol in the blood plasma.

    Children

    Associated with ivabradine

    Studies of interaction were studied only in adults.

    Special instructions:

    Patients with moderate hepatic impairment

    With moderate hepatic insufficiency (less than 9 on the Child-Pugh scale), Implicor® should be treated with caution.

    Lack of positive effect on clinical outcomes in patients with stable angina

    Implicore® is indicated only as a symptomatic therapy for stable angina pectoris, since ivabradine does not have a positive effect on the incidence of cardiovascular events (eg, myocardial infarction or death due to cardiovascular causes) in patients with angina pectoris (see the section "Pharmacodynamics").

    Heart Rate Control

    Given the significant variability of heart rate during the day, the determination of heart rate at rest in patients taking ivabradine, when making a decision on dose adjustment should be performed by one of these methods: serial measurement of heart rate, ECG or 24-hour outpatient monitoring of ECG. Such a determination should also be made to patients with low heart rate, in particular,if the heart rate drops below 50 bpm, or with a lower dose (see section "Method of administration and dose").

    Heart rhythm disturbances

    Ivabradine is ineffective for the treatment or prevention of arrhythmias and, probably, its effectiveness decreases with the development of tachyarrhythmias (eg, ventricular or supraventricular tachycardia). Therefore, Implicor® is not recommended for patients with atrial fibrillation or other types of arrhythmias associated with sinus node function.

    In patients receiving ivabradine, increased risk of developing atrial fibrillation (see section "Side effect"). Atrial fibrillation was more common among patients who simultaneously took ivabradine amiodarone or antiarrhythmic drugs I class. Against the background of Implicor®, regular clinical observation of patients is necessary to detect atrial fibrillation (paroxysmal or persistent) in a timely manner. For clinical indications (for example, worsening of the course of angina, the appearance of a palpitation, irregular heart rate), ECG should be included in the monitoring methods.Patients should be informed about the signs and symptoms of atrial fibrillation, and in case of such symptoms it is recommended to immediately consult your doctor. If atrial fibrillation occurred during the treatment period, the ratio of expected benefit to possible risk with further ivabradine application should be carefully analyzed again.

    Patients with CHF and intraventricular conduction abnormalities (left or right bundle branch block) and ventricular dissynchrony should be closely monitored.

    Use in patients with low heart rate

    The use of Implicor® is contraindicated if the heart rate at rest is less than 70 beats / min before the onset of therapy.

    If Implicor® therapy is persistently reduced at rest less than 50 beats per minute, or the patient has symptoms associated with bradycardia (such as dizziness, fatigue or hypotension), it is necessary to reduce the dose of the drug, switching to taking medications based on mono-components, until the optimal dose of metoprolol is reached, or cancel treatment (see "Method of administration and dose").

    Combined use with blockers of "slow" calcium channels (BCCC)

    The use of the drug together with BCCC, reducing heart rate, such as verapamil or diltiazem, is contraindicated (see section "With caution", "Interaction with other medicinal products").

    There was no change in the safety profile in the combined use of ivabradine with nitrates and BCCC-derived dihydropyridine derivatives, such as amlodipine. There is no additional efficacy of ivabradine when combined with dihydropyridine BCCI (see the section "Pharmacodynamics").

    Chronic heart failure

    During the prescription period Implicor® the condition of patients suffering from CHF. should be stable. In patients with CHF IV FK (functional class) according to the classification NYHA Implicor® should be used with caution, as the data on the use of the drug in this group of patients is limited.

    Stroke

    It is not recommended to prescribe Implicor® immediately after a stroke; data on the use of the drug in these patients are absent.

    Atrioventricular block (AV) I degrees

    In patients with AV blockade of I degree drug therapy Implicor® should be conducted with caution.

    Severe renal impairment (creatinine clearance less than 15 mL / min)

    Caution should be exercised when using Implicor® in patients with severe renal failure.

    Functions of visual perception

    Ivabradine affects the function of the retina (see the section "Pharmacodynamics"). At present, toxic effects of ivabradine on the retina of the eye have not been detected with prolonged use. In the event of sudden visual impairment, consideration should be given to stopping the Implicor® drug. Patients with retinitis pigmentosa degeneration (retinitis pigmentosa) the drug should be taken with caution (see section "With caution").

    Abolition of therapy

    You can not abruptly abolish beta-blockers, especially in patients with coronary heart disease. The discontinuation of Imprintor® should be accompanied by the simultaneous administration of metoprolol in the form of a monocomponent drug at the optimal dose for the patient.Reception of ivabradine can be stopped abruptly. The dose of metoprolol should be reduced gradually, preferably for at least 2 weeks, at the same time initiating replacement therapy, if necessary. If the patient has any symptoms, the dose reduction should be more gradual.

    Arterial hypotension

    Due to the lack of clinical data on ivabradine in patients with mild to moderate arterial hypotension, Implicor® should be administered with caution to these patients. Implicor® is contraindicated in severe arterial hypotension (systolic blood pressure less than 90 mmHg and diastolic blood pressure less than 50 mmHg) (see section "Contraindications").

    Atrial fibrillation - cardiac arrhythmias

    There is no evidence of an increased risk of developing severe (severe) bradycardia in restoring sinus rhythm after pharmacological cardioversion in patients taking ivabradine. However, due to the lack of sufficient data, scheduled electrical cardioversion should be performed no earlier than 24 hours after the last dose of ivabradine.

    The use of an elongated interval in patients with congenital syndrome QT or in patients taking drugs, lengthening the interval QT

    Implicor® should not be prescribed with a congenital syndrome of an elongated QT, as well as in combination with drugs that extend the interval QT (see section "Interaction with other drugs"). If necessary, such therapy should be ensured by continuous cardiomonitoring (see section "Special instructions"). The decrease in heart rate caused by ivabradine may aggravate the lengthening of the interval QT, which, in turn, can serve as a triggering factor for severe cardiac rhythm disturbances, including ventricular pirouette tachycardia.

    Use in patients with hypertension. who need a change in antihypertensive therapy

    There are data that during the treatment with ivabradine 7.1% of the patients had episodes of LD increase compared with 6.1% in patients taking placebo. These episodes were observed, as a rule, shortly after the change in antihypertensive therapy, were of a short-term nature and did not have a significant effect on the action of ivabradine. In patients with chronic heart failure receiving ivabradine, the change in therapy should be accompanied by regular blood pressure control.

    Use in patients with bronchial asthma and COPD (chronic obstructive pulmonary disease)

    Although metoprolol is a cardioselective beta-blocker, it should be used with caution in patients with bronchial asthma and COPD.

    If necessary, bronchodilating agents should be administered that selectively stimulate beta-2-adrenergic receptors, for example terbutaline. If preparations of the group of selective beta-2-adrenomimetics are already being used, an increase in their dose may be required.

    Severe peripheral vascular disease

    In patients with peripheral arterial lesions (Raynaud's disease or syndrome, arteritis or chronic diseases of the lower extremity vessels), the use of beta-blockers can worsen the course of the disease. In such cases, Implicor® should be discontinued and individual doses of monocomponent drugs should be selected. Preferably, the appointment of cardioselective beta-blockers with partial agonist activity, however, and their use should be used with caution.

    Pheochromocytoma

    With a confirmed or suspected diagnosis of pheochromocytoma, beta-blockers should be used in combination with alpha-blockers.

    Patients with diabetes mellitus

    Implicor® should be used with caution in patients with diabetes mellitus, especially with insulin therapy or with oral hypoglycemic drugs. Patients should be warned that beta-blockers can hide (mask) some of the symptoms of hypoglycemia, including tachycardia. At the same time, symptoms such as drowsiness and sweating may not necessarily decrease, and increased sweating may even increase.

    Angina pectoris

    The use of beta-blockers can increase the duration and frequency of attacks of angina Prinzmetal. The use of cardioselective beta] - adrenoblockers is possible in the case of minimal and associated forms of the disease and only in combination with vasodilators.

    Psoriasis

    The use of beta-blockers can cause an exacerbation of the course of psoriasis. Patients with psoriasis or having a history of psoriasis may be prescribed beta-blockers only after a thorough assessment of the benefit-to-benefit ratiorisks.

    Thyrotoxicosis

    Symptoms of thyrotoxicosis can be masked when taking beta-blockers.

    General anesthesia

    Long-term treatment with beta-blockers, as a rule, should not be canceled before surgical intervention. The reduced ability of the myocardium to respond to adrenergic stimulation can increase the risk of complications of general anesthesia and surgical manipulation. An anesthesiologist should be warned about the treatment. If the abolition of the beta-blocker is still necessary, the drug is gradually taken off. Completely medication should be discontinued 48 hours before general anesthesia.

    In elderly patients (over 65 years of age)

    It is necessary to carefully monitor the clinical condition of elderly patients, because excessive reduction of blood pressure or heart rate can lead to insufficient blood supply of vital organs during the treatment with beta-blockers.

    Allergic reactions

    With caution should be used in patients who have a history of severe allergic reactions, as well as in patients receiving desensitizing therapy, t. there is a risk of more severe anaphylactic reactions.

    Metoprolol may increase sensitivity to allergens and increase the severity of anaphylactic reactions. The administration of epinephrine to patients receiving beta-blockers is not always accompanied by the desired therapeutic effect (see "Interaction with other drugs").

    Athletes

    It should be taken into account the possibility of obtaining positive doping test results in athletes using the Implicor® drug, which contains metoprolol.

    Effect on the ability to drive transp. cf. and fur:

    The data available for mono-components suggest the possible impact of the Implicor® drug on the ability to drive vehicles and work with mechanisms.

    Iwabradine can adversely affect the ability to drive. Patients should be warned that ivabradine can cause a transient change in brightness in a limited area of ​​the visual field (mainly in the form of phosphenes). The phenomenon of altered light perception can be provoked by a sudden change in the intensity of illumination, especially when traveling at night. Iwabradine does not affect the work with the mechanisms.In the postgistrict period, there were reports of difficulties driving the car because of symptoms from the side of the body of vision against the background of ivabradine.

    Metoprolol affects the ability to drive vehicles and work with mechanisms. Patients should be warned about possible unwanted symptoms (such as headache, dizziness, fatigue). In addition, these clinical symptoms may worsen when taking alcohol or changing therapy. When these symptoms appear, patients should refrain from performing activities that require concentration and high speed of psychomotor reactions.

    Form release / dosage:

    Film-coated tablets, 5 mg + 25 mg, 7.5 mg + 25 mg, 5 mg + 50 mg, 7.5 mg + 50 mg.

    Packaging:For 14 tablets per blister (PVC / Al). For 1,2, 4 and 6 blisters with instructions for medical use in a pack of cardboard.
    Storage conditions:

    At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004583
    Date of registration:20.12.2017
    Expiration Date:20.12.2022
    The owner of the registration certificate:Servier LaboratoriesServier Laboratories France
    Manufacturer: & nbsp
    Information update date: & nbsp22.01.2018
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