Implicor, 5 mg+25 mg 56 pcs

Mechanism of action

Ivabradine

Ivabradine is a heart rhythm slowing drug whose mechanism of action is the selective and specific inhibition of the I_f channels of the sinus node which control spontaneous diastolic depolarization in the sinus node and regulate heart rate. Ivabradine has a selective effect on the sinus node without affecting the timing of impulse conduction along the intrapatrial, atrial-ventricular and intraventricular conduction pathways and on myocardial contractility and ventricular repolarization. Ivabradine can also interact with retinal I_h channels, similar to the heart’s I_fchannels. They are involved in causing temporary changes in the visual perception system by altering the retinal response to bright light stimuli. Under provocative circumstances (e.g., rapid brightness change in the visual field), partial inhibition of I_h channels by ivabradine causes the phenomenon of change in light perception (phosphene). Phosphenes are characterized by a transient brightness enhancement in a limited area of the visual field.

Metoprolol

Metoprolol is a cardioselective blocker that blocks β₁-adrenoreceptors (located primarily in the heart) at doses significantly lower than those required to block β₂-adrenoreceptors (localized primarily in the peripheral vessels and bronchi). Metoprolol has no membrane-stabilizing and intrinsic sympathomimetic activity (ISA).

Pharmacodynamic properties

Ivabradine

The main pharmacological feature of ivabradine is the ability to decrease HR in a dose-dependent manner. We analyzed the dose-dependent decrease in HR by gradually increasing the dose of ivabradine to 20 mg 2 times per day and found a tendency to reach a “plateau” effect, which reduces the risk of bradycardia (HR <40 bpm) (see "Adverse events").

The degree of HR reduction is approximately 10 bpm at rest and during exercise when using the drug in the recommended doses. This decreases heart function and myocardial oxygen demand.

Ivabradine has no effect on intracardiac conduction, myocardial contractility (no negative inotropic effect) and ventricular repolarization. In clinical electrophysiological studies ivabradine had no effect on pulse conduction time along atrial-ventricular or intraventricular conduction pathways, as well as on corrected QT intervals.

In patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%), ivabradine was shown to have no effect on LVEF.

Methoprolol

Methoprolol reduces or blocks the effects of catecholamines on the heart, resulting in decreased HR, myocardial contractility, and cardiac output. It has antihypertensive effects both when standing and lying down and also prevents BP elevation during exercise.

Clinical efficacy and safety

Ivabradine

. The antianginal and anti-ischemic efficacy of ivabradine has been studied in 5 studies (three of which were conducted compared with placebo and one each with atenolol and amlodipine) in patients with stable chronic angina pectoris.

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

Ivabradine administration to patients taking atenolol at a dose of 50 mg once daily showed additional efficacy in all exercise tests at the decline of its pharmacological activity (12 hours after oral administration).

Ivabradine at the pharmacological activity decline (12 hours after ingestion) had no additional effect when added to amlodipine at a dose of 10 mg/day, whereas at its maximum activity ivabradine (3-4 hours after ingestion) its additional efficacy was proven.

. Ivabradine at pharmacological activity decline (12 h after oral administration) over a 6-week treatment period demonstrated statistically significant additional efficacy in achieving treatment response (defined as reduction in angina attacks to at least 3 per week and/or increase in time to ST-segment depression of 1 mm by at least 60 sec during treadmill exercise testing) when added to amlodipine at 5 mg once/day or to nifedipine at 30 mg once/day. No improvement in the efficacy of ivabradine, as assessed by achievement of secondary endpoints during exercise testing, has been shown at the decline of therapeutic activity, while efficacy has been shown at the peak of activity (3-4 h after oral ivabradine administration).

In clinical efficacy studies, the effects of ivabradine were fully sustained throughout the 3- and 4-month treatment periods. There were no signs of tolerance (decreased efficacy) during treatment, and no withdrawal syndrome was observed after discontinuation of treatment. The antianginal and antiischemic effects of ivabradine were associated with a dose-dependent decrease in HR, as well as with a significant decrease in the work product (HR × systolic BP), both at rest and during physical activity. The effect on BP and OPPS was insignificant and clinically insignificant.

Sustained HR slowing was noted in patients taking ivabradine for at least 1 year. No effect on carbohydrate metabolism and lipid profile was observed.

In patients with diabetes mellitus the efficacy and safety of ivabradine were similar to those in the general patient population.

In the study in patients with CHD without clinical manifestations of heart failure (LVEF greater than 40%) on maintenance therapy, therapy with ivabradine at doses higher than recommended (initial dose 7.5 mg 2 times/day (5 mg 2 times/day in patients over 75 years of age), which was then titrated to 10 mg 2 times/day), had no significant effect on the primary combined endpoint (death due to cardiovascular cause or development of nonfatal myocardial infarction). The incidence of bradycardia in the group of patients receiving ivabradine was 17.9%, in the placebo group – 2.1%. 71% of patients in the study were taking verapamil, diltiazem or potent CYP3A4 isoenzyme inhibitors.

In patients with angina class II or higher according to the classification of the Canadian Society of Cardiology, there was a small statistically significant increase in the number of cases of the primary combined endpoint when using ivabradine, which was not observed in the subgroup of all patients with angina (class I or higher). This study used a higher dose than the approved dose, which still does not explain the results.

In a study involving patients with stable angina and left ventricular dysfunction (LVEF less than 40%), 86.9% of whom received beta-adrenoblockers, there were no differences between the groups of patients who received ivabradine on standard therapy and placebo in the cumulative incidence of cardiovascular deaths, hospitalizations for acute myocardial infarction, hospitalizations for new cases of heart failure, or increased symptoms of chronic heart failure (CHF). In patients with symptomatic angina pectoris, there were no significant differences in the incidence of death due to cardiovascular cause or hospitalization due to nonfatal myocardial infarction or heart failure (the incidence was 12.0% in the ivabradine group and 15.5% in the placebo group, respectively).

Metoprolol

In patients with CHD, metoprolol reduces the frequency and severity of ischemic episodes and increases exercise tolerance. These beneficial effects of metoprololol may be due to decreased myocardial oxygen demand as a result of reduced HR and myocardial contractility.

The use in children and adolescents

The use of Implicor^® in children and adolescents aged less than 18 years has not been well studied (see section “Pharmacokinetics”).

Pharmacokinetics

The rate and degree of absorption of ivabradine and metoprolol when taken orally as part of Implicor

sup>® are not significantly different from the corresponding absorption rates and absorption rates when the two drugs are used alone.

Ivabradine

Ivabradine is rapidly released from the tablet under physiologic conditions and is well soluble in water (solubility greater than 10 mg/ml). Ivabradine is an S-enantiomer, with no bioconversion according to in vivo studies. The main active metabolite of the drug is N-desmethylated derivative of ivabradine.

Ivabradine absorption and bioavailability

After oral administration, ivabradine is quickly and almost completely absorbed from the gastrointestinal tract. C_max in plasma is reached approximately 1 h after oral administration on an empty stomach. Absolute bioavailability of film-coated tablets is approximately 40% due to the effect of “first passage” through the intestine and liver.

Eating increases absorption time by approximately 1 hour and increases exposure from 20% to 30%. To reduce exposure variability, it is recommended that the drug be taken concomitantly with meals (see section “Dosing regimen”).

Distribution

The binding to plasma proteins is approximately 70%. V_d in equilibrium in patients is about 100 l. C_max with long-term administration at a dose of 5 mg 2 times/day is 22 ng/ml (coefficient of variation, CV= 29%). Mean equilibrium plasma concentration is 10 ng/ml (CV=38%).

Metabolism

Ivabradine is largely metabolized in the liver and intestine by oxidation involving only the cytochrome P450 3A4 isoenzyme (CYP3A4). The main active metabolite is N-desmethylated derivative of ivabradine (S18982), which accounts for 40% of the administered dose of ivabradine. Metabolism of this active metabolite of ivabradine also occurs with the participation of CYP3A4 isoenzyme. Ivabradine has negligible affinity to CYP3A4 isoenzyme, does not induce or inhibit it and, therefore, has no effect on the metabolism or plasma concentration of CYP3A4 isoenzyme substrates. On the contrary, the use of potent inhibitors or inducers of CYP3A4 isoenzyme may be accompanied by significant changes in the plasma concentration of ivabradine (see section “Drug interactions”).

The T_1/2 of ivabradine from plasma averages 2 hours (70-75% AUC) and effective T_1/2 is 11 hours. Total clearance is approximately 400 ml/min, renal clearance is 70 ml/min. Metabolites are excreted at the same rate by the kidneys and through the intestine. About 4% of the taken dose is excreted unchanged by the kidneys.

The linearity/non-linearity of pharmacokinetics

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

Particular patient groups

Patients who are elderly. Pharmacokinetic parameters (AUC and C_max) are not significantly different in the groups of patients 65 years and older, 75 years and older, and in the general patient population (see section “Dosing regimen”).

Renal dysfunction. The effect of decreased renal function (CK of 15 to 60 ml/min) on the kinetics of ivabradine is minimal, because only about 20% of ivabradine and its active metabolite S18982 are excreted by the kidneys (see section “Dosing regimen”).

Hepatic impairment. In patients with mild hepatic impairment (up to 7 points on the Child-Pugh scale) the AUC of free ivabradine and its active metabolite is 20% higher than in patients with normal hepatic function. Data on use of ivabradine in patients with moderate (7-9 Child-Pugh scores) hepatic impairment are limited and do not allow to make a conclusion about the peculiarities of pharmacokinetics of the drug in this group of patients. There are currently no data on the use of ivabradine in patients with severe (10 points or more on the Child-Pugh scale) hepatic impairment (see sections “Contraindications” and “Dosing regimen”).

The relationship between pharmacokinetic and pharmacodynamic properties

Analysis of relationship between pharmacokinetic and pharmacodynamic properties has established that decrease of HR is in direct proportion to increase of concentration of ivabradine and its active metabolite S18982 in blood plasma when taking in doses up to 15-20 mg 2 times daily. At higher doses of the drug, the slowing of heart rate does not have a proportional relationship with the plasma concentration of ivabradine and is characterized by a tendency to reach a “plateau”. High concentrations of ivabradine, which can be achieved when combining the drug with potent CYP3A4 isoenzyme inhibitors, may lead to a pronounced decrease in heart rate. When combined with moderate CYP3A4 isoenzyme inhibitors, this risk is lower (see sections “Contraindications”, “Drug Interactions” and “Cautions”).

Metoprolol

Intestation and distribution

Metoprolol is completely absorbed from the gastrointestinal tract after oral administration. C_max in plasma is reached 1.5-2 hours after ingestion. Because of the “first pass” effect through the liver, the bioavailability is approximately 50% when taken orally at a single time. Simultaneous intake of food increases bioavailability by about 30-40%. Binding to plasma proteins is insignificant (5-10%).

Metabolism

Metoprolol is metabolized in the liver by oxidation. The three known major metabolites of metoprolol have no significant beta-adrenoblocking activity.

The CYP2D6 isoenzyme is primarily, but not exclusively, involved in the metabolism of the drug. Due to the polymorphism of the CYP2D6 isoenzyme gene, the metabolic rate of metoprolol in patients exhibits interindividual variability. Patients with low metabolic rate (7-8%) have higher plasma concentrations of metoprolol and slower excretion compared to patients with high metabolic rate.

Elimation

The concentration after oral administration in plasma is constant and reproducible individually in patients, however, more than 95% of metoprolol and its metabolites are excreted through the kidneys, in unchanged form – about 5%, in some cases – up to 30%. T_1/2 is about 3.5 h (1 to 9 h). Plasma clearance is approximately 1 L/min.

Particular patient groups

The pharmacokinetic parameters (AUC and C_max) do not differ significantly between elderly (65 years and older) and younger patients.

Liver function impairment. Bioavailability of metoprolol increases and its excretion rate decreases.

The use in pregnancy and during breastfeeding. Metoprololol penetrates the placental barrier. The average ratio of metoprololol concentration in umbilical cord to maternal blood is 1. Metoprolol penetrates into breast milk. The concentration of metoprololol in breast milk can be 3.7 times higher than its concentration in maternal blood.

Indications

Symptomatic treatment of stable angina pectoris in adult patients with normal sinus rhythm, whose condition was adequately controlled using a combination of ivabradine and metoprolol monodrugs in the same doses.

Active ingredient

Ivabradine, Metoprolol

Composition

One film-coated tablet contains:

The active ingredients:

Ivabradine hydrochloride 5.39 mg (corresponding to 5 mg of ivabradine base) and metoprolol tartrate 25 mg;

B Excipients: Microcrystalline cellulose 71.37 mg, pregelatinized starch (corn) 48 mg, maltodextrin 8 mg, magnesium stearate 1.6 mg, colloidal anhydrous silica 0.64 mg;

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

How to take, the dosage

Implicor^® should be taken orally 1 tablet 2 times per day, in the morning and in the evening, with meals, with plenty of fluid. Plasma concentrations of metoprolol are increased when concomitantly taken with food (see section “Pharmacokinetics”). This fact should be considered when treating patients who have taken metoprolol on an empty stomach before prescribing Implicor^®.

The drug Implicor^® should only be prescribed in patients who are already taking ivabradine and metoprolol at optimal doses.

If necessary, adjust the dose with ivabradine and metoprolol monotherapy.

The decision to change the dosing regimen is recommended based on a number of assessments including HR, ECG or 24-hour Holter monitoring, and when the patient is stable on the optimal dose of metoprolol and ivabradine.

If there is no reduction of angina symptoms within 3 months of initiating treatment, Implicor® treatment should be discontinued.

If during treatment the resting HR falls below 50 bpm or if the patient develops symptoms characteristic of bradycardia (dizziness, increased fatigue or decreased BP), the dose of the drug should be reduced by selecting a new dose for monocomponent drugs to ensure an optimal dose of metoprolol. After dose reduction of ivabradine and metoprolol monocomponents, HR should be monitored (see section “Special Precautions”). Treatment should be discontinued if HR remains below 50 bpm or bradycardia symptoms persist despite dose reduction.

Patients with renal insufficiency with a CKR greater than 15 ml/min do not require a change in the dose of Implicor^®. If CKD is lower than 15 ml/min, the drug should be used with caution.

The drug Implicor^® may be used in patients with mild hepatic impairment. Caution should be exercised when using Implicor^® in patients with moderate hepatic insufficiency. The drug is contraindicated in patients with severe hepatic impairment (see sections “Pharmacokinetics” and “Contraindications”).

In elderly patients over 65 years of age, use Implicor^® with caution (see “Contraindications” subsection “With caution”).

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

Interaction

In studies of interaction between ivabradine and metoprolol in healthy volunteers, no mutual influence on the effects of each of the active substances has been established. Information about possible interactions with other medicinal products is given below.

Contraindications to concomitant use

Involved with ivabradine

. Simultaneous use of ivabradine with potent CYP3A4 isoenzyme inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, jozamicin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contraindicated (see Contraindications). Powerful inhibitors of CYP3A4 isoenzyme – ketoconazole (200 mg 1 time/day) or josamycin (1 g 2 times/day) increase average concentrations of ivabradine in plasma by 7-8 times.

Related with metoprolol

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

Related with ivabradine and metoprolol

Moderate CYP3A4 isoenzyme inhibitors: co-administration of ivabradine and diltiazem or verapamil (heart rate-lowering agents) in healthy volunteers and patients was accompanied by a 2-3-fold increase in ivabradine AUC and an additional reduction in HR by 5 bpm./min. This combination of drugs is contraindicated (see section “Contraindications”).

Slow calcium channel blockers (SCBs), such as verapamil or diltiazem, when administered by IV may increase the hypotensive effect of beta-adrenoblockers, exacerbating the effect on HR, AV conduction and myocardial contractility. Negative inotropic and chronotropic effects may increase. Therefore, during treatment with beta-adrenoblockers, intravenous administration of BMCCs is contraindicated (see section “Contraindications”).

Unwanted drug combinations

Bound with ivabradine

Drugs that prolong the QT interval

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• Antiarrhythmic drugs that prolong the QT interval (e.g., quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone);
• Drugs that prolong the QT interval and are not antiarrhythmic (e.g., pimozide, ziprazidone, certindole, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for IV administration).

The concomitant use of ivabradine and these drugs should be avoided because the decrease in HR may cause additional prolongation of the QT interval. ECG values should be monitored carefully if concomitant use of these drugs is necessary (see section “Special Precautions”).

Grapefruit juice: A 2-fold increase in the blood concentration of ivabradine has been observed with grapefruit juice. Grapefruit juice should be avoided if possible during the therapy with the drug.

Related with metoprolol

The following combinations with metoprolol should be avoided

Barbiturates: concomitant use of phenobarbital has proven to significantly increase metabolism of metoprolol through enzyme induction. Reduced plasma concentrations of metoprolol and, consequently, a decrease in its therapeutic effect (more active hepatic metabolism) were observed against the background of phenobarbital use.

Centrally acting hypotensive agents (e.g., clonidine): significant BP elevation is possible with abrupt withdrawal of centrally acting drugs. Central antihypertensive medications should not be stopped abruptly. Abrupt withdrawal from these drugs, especially if it preceded beta-adrenoblocker withdrawal, may increase the risk of withdrawal syndrome.

The simultaneous use of clonidine and non-selective beta-adrenoblockers, possibly selective beta-adrenoblockers, increases the risk of withdrawal syndrome. If clonidine is taken at the same time, it should be continued for some time if the beta-adreno-blocker is withdrawn.

The class I antiarrhythmic drugs (e.g., quinidine, tocainide, procainamide, amylmaline, amiodarone, flecainide, and disopyramide).

Beta-adrenoblockers may increase the negative inotropic effects of antiarrhythmic drugs and increase intraatrial conduction time. In patients with sinus node dysfunction, concomitant use with amiodarone may be accompanied by increased electrophysiological effects, with the development of bradycardia, sinus node block and AV block. T_1/2 amiodarone is very long (about 50 days), so after its withdrawal the interaction of drugs may manifest clinically after a long period of time. Class I antiarrhythmic drugs such as quinidine, tocainide, procainamide, amylmaline, amiodarone, flecainide, and disopyramide potentiate the effects of metoprolol on HR and AV conduction.

Companion use with caution

Bound with ivabradine

Non-potassium-saving diuretics (thiazide and “loop” diuretics): hypokalemia may increase the risk of arrhythmias. Because ivabradine can cause bradycardia, the combination of hypokalemia and bradycardia may predispose to severe arrhythmias, especially in patients with prolonged QT syndrome, whether prolonged QT interval is congenital or due to medication.

Moderate CYP3A4 inhibitors: Ivabradine in combination with other moderate CYP3A4 inhibitors (e.g. fluconazole) may be used with the minimum dose of 2.5 mg 2 times daily in those patients who have a resting HR greater than 70 bpm with HR control.

CYP3A4 isoenzyme inducers: (such as rifampicin, barbiturates, phenytoin and St. John’s wort) when used together may decrease the blood concentration and activity of ivabradine and may require increasing the dose of ivabradine. Co-administration of ivabradine 10 mg twice daily and preparations containing St. John’s wort showed a twofold decrease in the AUC of ivabradine. Do not use preparations containing St. John’s wort during therapy with ivabradine.

Related with metoprolol

Metoprolol is a substrate of the CYP2D6 isoenzyme of cytochrome P450. Substances that induce and inhibit the enzymes may change the plasma concentration of metoprolol.

Rifampicin decreases the plasma concentration of metoprolol.

Cimetidine, drugs containing ethanol, hydralazine may increase the plasma concentration of metoprolol. Metoprololol is metabolized primarily in the liver, but not exclusively, with the participation of CYP2D6 isoenzyme.

. Drugs that inhibit the CYP2D6 isoenzyme, such as selective serotonin reuptake inhibitors such as paroxetine, fluoxetine and sertraline, as well as diphenhydramine, hydroxychloroquine, celecoxib, terbinafine, drugs of the neuroleptic group (e.g., chlorpromazine, triflupromazine, chlorprotixen), and possibly propafenone, may increase plasma concentrations of metoprolol.

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

Methoprolol may decrease excretion of other drugs (e.g., lidocaine).

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

The dose of metoprolol may need to be decreased if the following groups of drugs are started:

• Nitrates – due to the risk of increasing the hypotensive effect of metoprolol;
• Cardiac glycosides (digoxin) – when taken simultaneously with beta-adrenoblockers, may slow the speed of AV conduction and cause bradycardia;
• .Beta-adrenoblockers (e.g., eye drops) and MAO inhibitors – close monitoring of patients is recommended because concomitant use with beta-adrenoblockers increases the risk of bradycardia and increased hypotensive effects;
• Adrenaline: If, under certain circumstances, patients receiving beta-adrenoblockers need adrenaline administration, it should be borne in mind that the hypotensive effect is significantly less pronounced with cardioselective beta-adrenoblockers than with non-selective ones.

– Parasympathomimetics: Simultaneous use of parasympathomimetics may cause prolonged bradycardia: concomitant administration of NSAIDs, such as indomethacin, may reduce the antihypertensive effects of metoprolol;

– Insulin and oral antidiuretics: metoprolol may increase the hypoglycemic effect of oral hypoglycemic drugs and may result in masking the symptoms of hypoglycemia. It may be necessary to change the dose of oral hypoglycemic drugs.

Drug combinations to consider

Ivabradine-related

It has been shown that there is no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine when the following drugs are used simultaneously: Proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), dihydropyridine derivatives of the BMCC series (amlodipine, latsidipine), digoxin and warfarin. It has been 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.

The safety profile of ivabradine with: Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, beta-adrenoblockers, diuretics, aldosterone antagonists, short- and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, oral hypoglycemic agents, acetylsalicylic acid and other antiaggregants.

Cytochrome P4503A4 (CYP3A4 isoenzyme): Ivabradine is metabolized in the liver via CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. Ivabradine has no significant effect on the metabolism and plasma concentrations of other substrates (potent, moderate and weak inhibitors) of CYP3A4 isoenzyme. At the same time, inhibitors and inducers of CYP3A4 isoenzyme may interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It was found that CYP3A4 isoenzyme inhibitors increase and CYP3A4 isoenzyme inducers decrease the plasma concentration of ivabradine. Increasing the plasma concentration of ivabradine may increase the risk of marked bradycardia (see section “Cautions”).

Triggered by metoprolol

Concomitant use of tricyclic antidepressants and neuroleptics may be accompanied by increased antihypertensive effects and an increased risk of orthostatic hypotension (additive effect).

The concomitant use of Mefloquine may be accompanied by a risk of severe bradycardia (additive effect).

The simultaneous intravenous administration of dipyridamole may increase the antihypertensive effect.

The alpha-adrenoblockers used in urology (alfuzosin, doxazosin, prazosin, tramzulosin, terazosin) may increase the hypotensive effect of metoprolol and increase the risk of orthostatic hypotension.

Ergotamine (when taken together, may increase vasoconstriction).

Curare-like muscle relaxants (increased neuromuscular blockade).

Floktafenin: beta-adrenoblockers may interfere with the compensatory cardiovascular response associated with arterial hypotension or shock, which may develop with floktafenin.

Antacids – concomitant administration has been associated with increased plasma concentrations of metoprolol.

In children

Bound with ivabradine

Interaction studies have only been studied in adults.

Special Instructions

Patients with moderate hepatic impairment

In moderate hepatic impairment (less than 9 points on the Child-Pugh score), therapy with Implicor^® should be used with caution.

Lack of benefit on clinical outcomes in patients with stable angina

The use of Implicor^® is indicated only as symptomatic therapy for stable angina, because ivabradine has no beneficial effect on the incidence of cardiovascular events (e.g., myocardial infarction or death due to cardiovascular causes) in patients with angina.

Performance monitoring

With the significant variability in resting heart rate during the day, resting heart rate determination in patients taking ivabradine should be performed in one of the following ways: serial heart rate measurement, ECG or 24-hour ambulatory ECG monitoring when deciding whether to adjust the dose. This determination should also be made in patients with low HR, particularly if the HR falls below 50 bpm, or when the dose is reduced (see Dosing regimen).

Heart rhythm disorders

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

Patients taking ivabradine have an increased risk of developing atrial fibrillation (see section “Side effects”). Atrial fibrillation was more common among patients who concomitantly took amiodarone or class I antiarrhythmic drugs with ivabradine. Against the background of the drug Implicor^® regular clinical monitoring of patients for the timely detection of atrial fibrillation (paroxysmal or permanent) is necessary. When clinically indicated (e.g., worsening angina, palpitations, irregular heart rhythm), ECG should be included in the monitoring methods. Patients should be informed about the signs and symptoms of atrial fibrillation, and if such symptoms appear, they should be advised to contact their attending physician immediately. If atrial fibrillation has occurred during treatment, the ratio of expected benefit to possible risk during further use of ivabradine should be carefully analyzed again.

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

The use in patients with low HR

The use of Implicor^® is contraindicated if the resting HR is less than 70 bpm before therapy.

If, during therapy with Implicor^® there is a persistent decrease in resting HR of less than 50 bpm, or the patient develops symptoms associated with bradycardia (such as dizziness, increased fatigue, or hypotension), the drug dose should be reduced by switching to monocomponent drugs until an optimal dose of metoprolol is achieved, or treatment should be stopped.

Combined use with slow calcium channel blockers (CMBs)

The drug is contraindicated with CMBs that lower heart rate, such as verapamil or diltiazem.

There has been no change in the safety profile when combining ivabradine with nitrates and dihydropyridine derivative BMCCs such as amlodipine. No additional efficacy of ivabradine when combined with dihydropyridine-derived BMCCs has been found.

Cronic Heart Failure

At the time of Implicor^® prescription, the condition of patients with CHF should be stable. In patients with CHF class IV according to NYHA classification Implicor^® is recommended with caution since data about use of the drug in this group of patients are limited.

Stroke

The use of Implicor^® immediately after a stroke is not recommended because there are no data on its use in these patients.

In patients with AV block of 1st degree

The therapy with Implicor^® should be used with caution.

Severe renal impairment (CKG less than 15 ml/min)

Cautious use of Implicor^® in patients with severe renal impairment should be observed.

Vabrady affects visual function

Ivabrady affects the function of the retina. No toxic effects of ivabradine on the retina have been identified with long-term use. If unexpected visual impairment occurs, discontinuation of the drug Implicor^® should be considered. Patients with retinal pigmentary degeneration (retinitis pigmentosa) should take the drug with caution.

Cancellation of therapy

Beta-adreno-blockers should not be abruptly withdrawn, especially in patients with CHD. Discontinuation of Implicor^® should be accompanied by simultaneous administration of metoprolol as a mono-component drug at the optimal dose for the patient. Administration of ivabradine may be stopped abruptly. The metoprolol dose should be reduced gradually, preferably over at least 2 weeks, while starting substitution therapy, if necessary. If the patient develops any symptoms, the dose reduction should be more gradual.

Arterial Hypotension

Because of the paucity of clinical data on the use of ivabradine in patients with mild to moderate arterial hypotension, Implicor^® should be prescribed with caution in these patients. Implicor^® is contraindicated in severe arterial hypotension (systolic BP less than 90 mm Hg and diastolic BP less than 50 mm Hg).

Atrial fibrillation – cardiac arrhythmias

There is no evidence of increased risk of significant (severe) bradycardia during resuscitation of sinus rhythm after pharmacological cardioversion in patients taking ivabradine. However, due to insufficient data, electrically-guided planned cardioversion should not be performed earlier than 24 h after the last dose of ivabradine.

The use in patients with congenital prolonged QT interval syndrome or in patients taking drugs that prolong the QT interval

ImplicorThe use in patients with congenital prolonged QT interval syndrome or in patients taking drugs that prolong the QT interval.

Implicor^® should not be administered in congenital long QT syndrome or in combination with drugs that prolong the QT interval (see see section “Drug interactions”). If such therapy is necessary, continuous cardiac monitoring should be provided. Reduction of HR caused by ivabradine may exacerbate QT interval prolongation, which in turn may serve as a trigger for severe heart rhythm disturbances, including pirouette-type ventricular tachycardia.

Application in patients with arterial hypertension who require a change in antihypertensive therapy

There is evidence that during treatment with ivabradine, 7.1% of patients had episodes of BP elevation compared to 6.1% of patients taking placebo. These episodes were usually observed shortly after changing antihypertensive therapy, were of short duration, and had no significant effect on the effect of ivabradine. In patients with chronic heart failure receiving ivabradine, a change in therapy should be accompanied by regular BP monitoring.

The use in patients with bronchial asthma and COPD

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

Bronchodilators that selectively stimulate β₂ adrenoreceptors, such as terbutaline, should be prescribed if necessary. If drugs of the group of selective beta₂-adrenomimetics are already in use, an increase in their dose may be necessary.

Severe peripheral vascular disease

In patients with peripheral arterial disease (Raynaud’s disease or syndrome, arteritis, or chronic lower extremity vascular disease) the use of beta-adrenoblockers may worsen the disease. In such cases, Implicor^® should be discontinued and individual doses of monocomponent drugs should be selected. Administration of cardioselective beta-adrenoblockers with partial agonist activity is preferable, but they should also be used with caution.

Pheochromocytoma

Beta-adrenoblockers should be used in combination with alpha-adrenoblockers if the diagnosis of pheochromocytoma is confirmed or suspected.

Patients with diabetes mellitus

Implicor^® should be used with caution in patients with diabetes mellitus, especially on insulin therapy or treatment with oral hypoglycemic agents. Patients should be warned that beta-adrenoblockers may hide (mask) some 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.

Prinzmetal angina

The use of beta-adrenoblockers may increase the duration and frequency of Prinzmetal angina attacks. The use of cardioselective beta₁-adrenoblockers is possible in minimal and associated forms of the disease and only in combination with vasodilators.

Psoriasis

The use of beta-adrenoblockers may cause exacerbation of the course of psoriasis. In patients with psoriasis or a history of psoriasis, beta-adrenoblockers should be prescribed only after careful assessment of benefit-risk ratio.

Thyrotoxicosis

The symptoms of thyrotoxicosis may be masked by the administration of beta-adrenoblockers.

General anesthesia

Long-term treatment with beta-adrenoblockers usually should not be reversed before surgery. Reduced ability of the myocardium to respond to adrenergic stimulation may increase the risk of complications of general anesthesia and surgical manipulation. The anesthesiologist should be alerted to the ongoing treatment. If beta-adrenoblocker withdrawal is still necessary, the drug should be discontinued gradually. Completely discontinue the drug 48 hours prior to general anesthesia.

In elderly patients (>65 years of age),

The clinical condition of elderly patients must be monitored closely because excessive BP or HR reduction may result in insufficient blood supply to vital organs during treatment with beta-adrenoblockers.

Allergic reactions

The drug should be used with caution in patients with a history of severe allergic reactions and in patients receiving desensitization therapy, since there is a risk of more severe anaphylactic reactions.

Metoprolol may increase sensitivity to allergens and exacerbate the severity of anaphylactic reactions. Administration of adrenaline to patients receiving beta-adrenoblockers is not always accompanied by the desired therapeutic effect (see section “Drug Interactions”).

In athletes

The possibility of positive doping test results in athletes using Implicor®, which contains metoprolol, must be considered.

The effect on driving and operating ability

The data available for monocomponents suggest a possible effect of the drug Implicor^® on the ability to drive vehicles and operate mechanisms.

Ivabradine may have an adverse effect on the ability to drive. Patients should be cautioned that ivabradine may cause transient changes in brightness in a limited area of the visual field (mainly in the form of phosphenes). The phenomenon of altered light perception may be provoked by an abrupt change in light intensity, especially when traveling at night. Ivabradine has no effect on operating machinery. In the post-registration period there have been reports of difficulty driving due to visual symptoms while taking ivabradine.

Methoprolol has an effect on the ability to drive vehicles and operate machinery. Patients should be warned about possible undesirable symptoms (such as headache, dizziness, increased fatigue). In addition, these clinical symptoms may worsen in the background of alcohol intake or changes in therapy. If the above symptoms occur, patients should refrain from performing activities requiring concentration and high speed of psychomotor reactions.

Contraindications

• high sensitivity to ivabradine, metoprolol (and other drugs of the beta-adrenoblocker group due to possible cross-sensitivity), as well as to the excipients in the drug;
• explicit or symptomatic bradycardia (see Dosing regimen.
• acute or symptomatic bradycardia (see
• Dosing regimen
• cardiogenic shock
• acute myocardial infarction or suspected acute myocardial infarction complicated by severe bradycardia, grade I AV block, hypotension (systolic BP <100 mmHg), and/or severe cardiac arrest

.BP less than 100 mmHg) and/or severe heart failure;

• CCSU (including sinoatrial block);
• AV block of degree II and III;
• severe arterial hypotension (BP less than 90/50 mmHg) or symptomatic arterial hypotension;
• unstable or acute heart failure;
• in patients receiving intermittent short-term treatment with beta-adrenomimetics;
• unstable angina;
• severe peripheral vascular disease;
untreated pheochromocytoma;
• severe hepatic insufficiency;
• metabolic acidosis;
• concomitant use with potent CYP3A4 isoenzyme inhibitors, such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, jozamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see “Pharmacokinetics” sections).
• concomitant use with verapamil or diltiazem as they are moderate CYP3A4 isoenzyme inhibitors and have the ability to decrease HR (see Drug Interactions). Pregnancy and lactation;
• Breastfeeding (see section on Pregnancy and lactation);
• Application in women of childbearing potential who are not using reliable contraception.
• Application in women of preserved fertile potential who are not using reliable contraceptive methods (see “Pregnancy and lactation”);
• Age under 18 years (effectiveness and safety in this age group have not been studied).

With caution

In patients with: moderate hepatic impairment (less than 9 points on the Child-Pugh scale); mild to moderate arterial hypotension; congenital QT interval prolongation or concomitantly taking QT interval prolonging medications; Prinzmetal angina; bronchial asthma or COPD; grade 1 AV blockade; heart rhythm disorders; stroke; severe renal function impairment (CK less than 15 ml/min) arterial hypertension; chronic heart failure; obstructive pulmonary disease; diabetes, especially with concomitant use of insulin or oral antidiabetic agents; psoriasis; thyrotoxicosis; retinal pigment degeneration; severe hypersensitivity reactions in history and who received desensitization therapy, elderly (over 65 years) (see section “Cautionary Instructions. See section “Special Precautions”).

In: CHF and intraventricular conduction abnormalities (left or right bundle branch block) and ventricular dyssynchrony; CHF class IV by NYHA classification; concomitant use of amiodarone or powerful class I antiarrhythmic drugs; general anesthesia (see section “Special Precautions”).

Warnings regarding concomitant use with other medicinal products are listed in the section “Drug Interactions”.

Side effects

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

The most common adverse drug reactions (ADRs) with ivabradine were changes in light perception (phosphenes) and bradycardia. These ADRs were dose-dependent and related to the mechanism of action of the drug.

The most common HRs during treatment with metoprolol were: bradycardia, nightmares, headache, drowsiness, insomnia, dizziness, palpitations, orthostatic hypotension, cold extremities, Raynaud’s disease, shortness of breath on exercise, nausea, constipation, diarrhea, stomach pain, vomiting, increased fatigue, libido disturbance.

The table provides information on the NERs that have been noted with ivabradine and metoprolol separately and classified according to MedDRA. The following classification was used to indicate frequency: very common (≥1/10); common (≥1/100 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10 000 to < 1/1000); very rare (< 1/10 000); frequency not specified (cannot be determined from available data).

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* The frequency of side effects for spontaneous reports is calculated from clinical trial data.

Individual adverse reactions

Change in light perception (phosphenes) 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, these phenomena were provoked by an abrupt change in light intensity. Phosphenes may also occur in the form of areolae, disintegration of the visual picture into separate parts (stroboscopic and kaleidoscopic effects), appear as bright color flashes or multiple images (retinal persistence). Symptoms usually appear within the first 2 months of treatment and recur thereafter. The severity of phosphenes is usually mild to moderate. All symptoms ceased during or after completion of treatment, with 77.5% of patients having symptoms disappearing during the treatment period. Fewer than 1% of patients had to change their daily regimen or discontinue treatment with the drug because of their phosphenes.

Bradycardia was observed in 3.3% of patients, mostly during the first 2-3 months of treatment. Severe bradycardia with a HR of 40 bpm or less was observed in 0.5% of patients.

In a clinical trial, atrial fibrillation occurred in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group. In an analysis of pooled data from clinical studies with at least a 3-month follow-up period, involving more than 40,000 patients, atrial fibrillation occurred in 4.86% of patients taking ivabradine compared to 4.08% in the control groups.

Overdose

No cases of overdose of the drug Implicor^® have been reported.

The symptoms associated with ivabradine may include marked and prolonged bradycardia.

Symptoms associated with metoprolol: there may be a marked decrease in BP, sinus bradycardia, AV blockade, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, confusion, coma, nausea, vomiting, cyanosis of the skin and mucous membranes. Symptoms may increase with the simultaneous use of alcohol, taking antihypertensive drugs, quinidine-containing drugs, and barbiturates.

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

The treatment: in addition to general measures (gastric lavage within 4 hours after taking the drug and in case of severe intoxication, and taking activated charcoal), patients should be under observation in the ICU, where correction of vital signs is performed, if necessary.

In case of severe bradycardia, symptomatic therapy is indicated. In bradycardia with impaired hemodynamics, IV administration of beta-adrenomimetics, such as isoprenaline, is performed. If necessary, a temporary artificial pacemaker may be implanted. Atropine is a potential antidote to metoprolol (0.5-2 mg i.v.) and is preceded by intravenous glucagon (1-5 mg, but no more than 10 mg). In addition, sympathomimetics may be administered in doses adjusted for the patient’s body weight and taking into account the desired clinical effect (dobutamine, adrenaline). It may be necessary to use doses in excess of therapeutic doses.

In case of seizures, slow intravenous diazepam is recommended.