Implicor pills 5mg+50mg, 56pcs

Composition

One film-coated tablet contains:

• active ingredients:
• ivabradine hydrochloride 5.39 mg (corresponding to 5 mg of ivabradine base) and metoprolol tartrate 50 mg;
• excipients:
• microcrystalline cellulose 97.25 mg,
• pregelatinized starch (corn) 72 mg,
• maltodextrin 12 mg,
• magnesium stearate 2.4 mg,
• colloidal anhydrous silicon dioxide 0.96 mg;
• shell:
• glycerol 0.36288 mg, hypromellose 6.031872 mg, macrogol 6000 0.385152 mg, magnesium stearate 0.36288 mg, titanium dioxide 1.161216 mg

Pharmacological action

Mechanism of action

Ivabradin

Ivabradine is a drug that slows down the heart rate, the mechanism of action of which consists in 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 time of impulses along the intra-atrial, atrioventricular and intraventricular pathways, as well as the contractility of the myocardium and ventricular repolarization. Ivabradine can also interact with_{the ih} channels of the retina, similar_{to the}If channels of the heart. They are involved in the occurrence of temporary changes in the visual perception system due to changes in the retinal response to bright light stimuli. Under provoking circumstances (for example, a rapid change in brightness in the visual field), partial inhibition of ih channels by ivabradine causes the phenomenon of changing light perception (phosphene). Phosphenes are characterized by a transient increase in brightness in a limited area of the visual field.

Metoprolol

Metoprolol is a cardioselective blocker that blocks β1-adrenergic receptors (located mainly in the heart) at doses significantly lower than the doses required to block β2-adrenergic receptors (located mainly in peripheral vessels and bronchi). Metoprolol has no membrane-stabilizing or intrinsic sympathomimetic activity (ICA).

Pharmacodynamic properties

Ivabradin

The main pharmacological feature of ivabradine is the ability to reduce heart rate in a dose-dependent manner. The 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 to 20 mg 2 times / day and revealed a tendency to achieve a “plateau” effect, which reduces the risk of developing severe bradycardia (heart rate less than 40 beats/min) (see the section “Side effect”).

When prescribing the drug in the recommended doses, the degree of heart rate reduction is approximately 10 beats / min at rest and during physical exertion. As a result, the work of the heart decreases and the need for oxygen in the myocardium decreases.

Ivabradine does not affect intracardiac conduction, myocardial contractility (does not have a negative inotropic effect) and the process of ventricular repolarization. In clinical electrophysiological studies, ivabradine did not affect the timing of impulses along the atrioventricular or intraventricular pathways, as well as the adjusted QT intervals.

In patients with left ventricular dysfunction (left ventricular ejection fraction (LVEF) 30-45%), ivabradine was shown to have no effect on 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 rise of blood pressure during physical exertion.

Clinical efficacy and safety

Ivabradin

The anti-anginal and anti-ischemic efficacy of ivabradine was evaluated in 5 trials (three of which were conducted in comparison with placebo and one each in comparison with atenolol and amlodipine) in patients with stable chronic angina pectoris.

It was found that ivabradine at a dose of 5 mg 2 times / day improved the performance of exercise tests after 3-4 weeks of therapy. The efficacy was also confirmed for a dose of 7.5 mg 2 times / day. In particular, the additional effect of increasing the dose from 5 to 7.5 mg 2 times / day was established in a comparative study with atenolol. The exercise time increased by approximately 1 minute after 1 month of ivabradine 5 mg 2 times / day, while after an additional 3-month course of ivabradine 7.5 mg 2 times/day orally, a further increase in this indicator by 25 seconds was noted. The antianginal and anti-ischemic activity of ivabradine was also confirmed for patients aged 65 years and older. The efficacy of ivabradine at doses of 5 mg and 7.5 mg 2 times / day was observed in relation to all indicators of exercise tests (total duration of physical activity, time to limiting angina attack, time to the onset of angina attack and time to the development of ST-segment depression by 1 mm), and was accompanied by a decrease in the frequency of angina attacks by approximately 70%. The use of ivabradine 2 times / day provided constant therapeutic efficacy for 24 hours.

Ivabradine use in patients taking atenolol at a dose of 50 mg 1 time/day showed additional effectiveness in relation to all indicators of stress tests at the decline of its pharmacological activity (12 hours after oral use).

Ivabradine at a decrease in pharmacological activity (12 hours after oral use) did not have an additional effect when added to amlodipine at a dose of 10 mg/day, while at the maximum activity of ivabradine (3-4 hours after oral use), its additional effectiveness was proven.

Ivabradine, on the decline of pharmacological activity (12 hours after oral use) during 6-week treatment, demonstrated statistically significant additional effectiveness in achieving a response to treatment (defined as a reduction in angina attacks to at least 3 per week and/or an increase in the time to development of ST-segment depression by 1 mm for at least 60 seconds during a treadmill exercise test) when added to amlodipine at a dose of 5 mg 1 time/day or to nifedipine at a dose of 30 mg 1 time/day. There was no improvement in the effectiveness of ivabradine, as measured by the achievement of secondary endpoints during exercise tests, during the decline of therapeutic activity, while the effectiveness was shown at the maximum activity (3-4 hours after oral use of ivabradine).

In studies of the clinical efficacy of the drug, the effects of ivabradine were completely preserved during the 3-and 4-month treatment periods. During treatment, there were no signs of developing tolerance (reduced effectiveness), and after discontinuation of treatment, there was no “withdrawal” syndrome. The antianginal and anti-ischemic effects of ivabradine were associated with a dose-dependent decrease in heart rate, as well as a significant reduction in the work product (HR × systolic BP), both at rest and during exercise. The effect on blood pressure and OPSS was insignificant and clinically insignificant.

A steady decrease in heart rate was observed 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 indicators of ivabradine were similar to those in the general patient population.

In a study in patients with CHD without clinical manifestations of heart failure (LVEF more than 40%) on the background of maintenance therapy, ivabradine therapy at doses higher than recommended (an initial dose of 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), 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 was 17.9% in the ivabradine group and 2.1% in the placebo group. 71% of patients in the study were taking verapamil, diltiazem, or potent CYP3A4 inhibitors.

In patients with angina pectoris of 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 primary combined endpoint with ivabradine, which was not observed in the subgroup of all patients with angina pectoris (class I and higher). In this study, a higher dose was used than the approved dose, but this 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 were no differences between the groups of patients taking ivabradine on the background of standard therapy and placebo, in the total frequency of deaths from cardiovascular diseases, hospitalization for acute myocardial infarction, hospitalization for new cases of heart failure or increased symptoms of chronic heart failure (CHF). In patients with symptomatic angina, there were no significant differences in the incidence of death due to cardiovascular causes or hospitalization due to non-fatal 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 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.

Use in children and adolescents

The use of Implicor® in children and adolescents under 18 years of age has not been sufficiently studied (see section “Pharmacokinetics”).

Pharmacokinetics

Rate and degree of absorption of ivabradine and metoprolol when taken orally as part of Implikor® they do not differ significantly from the corresponding values of the rate and degree of absorption in cases where both drugs are used separately.

Ivabradin

Under physiological conditions, ivabradine is quickly released from the tablet and is well soluble in water (solubility is more 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 the N-desmethylated derivative of ivabradine.

Absorption and bioavailability

After oral use, ivabradine is rapidly and almost completely absorbed from the gastrointestinal tract. C_max in blood plasma is reached approximately 1 h after oral use on an empty stomach. The absolute bioavailability of film-coated tablets is approximately 40%, due to the “first pass” effect through the intestines and liver.

Food 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 simultaneously with a meal (see the section “Dosage regimen”).

Distribution

Binding to plasma proteins is approximately 70%. Vd atsteady state in patients is-about 100 l. S_max with long-term use at a dose of 5 mg 2 times / day is 22 ng / ml (coefficient of variation, CV= 29%). The average steady-state plasma concentration is 10 ng / ml (CV=38%).

Metabolism

Ivabradine is largely metabolized in the liver and intestines by oxidation involving only the cytochrome P450 3A4 isoenzyme (CYP3A4). The main active metabolite is the N-desmethylated derivative of ivabradine (S18982), which accounts for 40% of the administered dose of ivabradine. The metabolism of this active metabolite of ivabradine also occurs with the participation of the CYP3A4 isoenzyme. Ivabradine has a low affinity for the CYP3A4 isoenzyme, does not induce or inhibit it, and, as a result, does not affect the metabolism or concentration of substrates of the CYP3A4 isoenzyme in blood plasma. On the contrary, the use of powerful inhibitors or inducers of the CYP3A4 isoenzyme may be accompanied by a significant change in the concentration of ivabradine in blood plasma (see the section “Drug interaction”).

Elimination

of T_1/2 ivabradine from blood plasma is on average 2 hours (70-75% AUC), and the effective T_1/2 is 11 hours. Total clearance is approximately 400 ml / min, renal clearance is 70 ml / min. Excretion of metabolites occurs at the same rate by the kidneys and through the intestines. About 4% of the dose taken is excreted unchanged by the kidneys.

Linearity / non-linearity 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 and older,75 years and older, and in the general patient population (see the section “Dosage regimen”).

Impaired renal function. The effect of decreased renal function (creatinine clearance from 15 to 60 ml / min) on the kinetics of ivabradine is minimal, since only about 20% of ivabradine and its active metabolite S18982 are excreted by the kidneys (see the section “Dosage regimen”).

Impaired liver function. In patients with mild hepatic insufficiency (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 liver function. Data on the use of ivabradine in patients with moderate (7-9 points on the Child-Pugh scale) hepatic insufficiency are limited and do not allow us to conclude about the 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 insufficiency (see the sections “Contraindications” and “Dosage regimen”).

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 directly proportional to the increase in the concentration of ivabradine and its active metabolite S18982 in blood plasma when taken at 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 blood plasma and is characterized by a tendency to reach a “plateau”. High concentrations of ivabradine, which can be achieved by combining the drug with powerful inhibitors of the CYP3A4 isoenzyme, can lead to a pronounced decrease in heart rate. When co-administered with moderate inhibitors of the CYP3A4 isoenzyme, this risk is lower (see the sections “Contraindications”, “Drug interaction” and “Special Instructions”).

Metoprolol

Suction and distribution

After oral use, metoprolol is completely absorbed from the gastrointestinal tract. C_max in blood plasma is reached in 1.5-2 hours after use. Due to the “first pass” effect through the liver, bioavailability is approximately 50% with a single oral dose. Simultaneous food intake increases bioavailability by approximately 30-40%. The association with 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-blocking activity.

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

Deduction

The concentration after oral use in blood 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). The plasma clearance is approximately 1 l/min.

Special patient groups

Pharmacokinetic parameters (AUC and_cmax) do not differ significantly in elderly (65 years and older) and younger patients.

Impaired liver function. The bioavailability of metoprolol increases and the rate of its elimination decreases.

Use during pregnancy and lactation. Metoprolol penetrates the placental barrier. The average ratio of the concentration 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 can be 3.7 times higher than its concentration in the mother’s blood.

Indications

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

Contraindications

• hypersensitivity to ivabradine, the metoprolol (and other drugs of the group of beta-blockers in view of the possible cross-sensitivity), as well as auxiliary substances included in the composition of the drug;
• severe or symptomatic bradycardia (see section “dosage regimen”);
• cardiogenic shock;
• acute myocardial infarction or suspected acute myocardial infarction complicated by severe bradycardia, AV blockade of I degree, hypotension (systolic blood pressure less than 100 mm Hg. St. ) and/or severe heart failure;
• SSSU (including sinoatrial blockade);
• AV blockade II and III degree,
• severe hypotension (BP less than 90/50 mm Hg. St. ) or symptomatic hypotension;
• unstable or acute heart failure;
• patients periodically receiving short-term treatment with beta-agonists;
• patients dependent on a pacemaker (which heart rate is provided by only a constant cardioversion);
• unstable angina;
• severe peripheral vascular disease;
• untreated pheochromocytoma;
• severe hepatic impairment;
• metabolic acidosis;
• concurrent use with potent inhibitors of isoenzyme CYP3%^%A%^%4, such as antifungal agents of the group of azoles (ketoconazole, Itraconazole), the macrolide antibiotics (clarithromycin, erythromycin for oral use, josamycin, telithromycin), an HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone (see “Pharmacokinetics” and “Drug interactions”) ;
• concurrent use of verapamil or diltiazem, since they are related to moderate inhibitors of isoenzyme CYP3%^%A%^%4 and have the ability to reduce heart rate (see “Drug interactions”);
• pregnancy (see section “Pregnancy and lactation”);
• breast-feeding (see “Pregnancy and lactation”);
• the use of women with preserved reproductive potential who are not using reliable methods of contraception (see section “Pregnancy and lactation”);
• age up to 18 years (efficacy and safety of use in this age group has not been studied).

With caution

In patients with: moderate hepatic insufficiency (less than 9 points on the Child-Pugh scale); mild to moderate arterial hypotension; congenital prolongation of the QT interval or simultaneously taking medications that prolong the QT interval; Prinzmetal angina pectoris; bronchial asthma or COPD; Grade 1 AV block; cardiac arrhythmias; stroke; severe renal impairment (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; retinal pigmentation degeneration; severe hypersensitivity reactions in the anamnesis and receiving desensitizing therapy, the elderly (over 65 years) (see the section “Special instructions”).

By: Heart failure and intraventricular conduction disorders (left or right bundle branch block) and ventricular dyssynchrony; NYHA functional class IV CHF; concomitant use of amiodarone or powerful class I antiarrhythmic drugs; general anesthesia (see section “Special instructions”).

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

Side effects

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

Of the adverse drug reactions (NLR) associated with ivabradine use, the most common were: changes in light perception (phosphenes) and bradycardia. These NLRs were dose-dependent and were associated with the mechanism of action of the drug.

The most frequent NLRs during metoprolol treatment were: bradycardia, nightmares, headache, drowsiness, insomnia, dizziness, palpitations, orthostatic hypotension, cold extremities, Raynaud’s disease, shortness of breath during exercise, nausea, constipation, diarrhea, abdominal pain, vomiting, increased fatigue, impaired libido.

The table below provides information on NLRs that were observed when ivabradine and metoprolol were used separately, and classified according to MedDRA. The following classification is 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 (

Adverse reaction(in MedDRA terminology)	Frequency
	Ivabradin	Metoprolol
From the blood and lymphatic system
eosinophilia	infrequently	–
thrombocytopenia	–	rarely
leukopenia	–	very rarely
From the immune system
, psoriasis exacerbation	is	infrequent
From the side of metabolism and nutrition
hyperuricemia	infrequently	–
hypoglycemia	–	infrequently
Mental disorders
depression	–	infrequently
nightmares, abnormal dreams	–	often
increased excitability	–	rarely
anxiety	–	rarely
confusion	–	infrequently
hallucinations	–	infrequently
depersonalization	–	very rarely
From the nervous system
headache	often	often
amnesia	–	very rarely
slowing down the speed of mental and motor reactions, comprehension	–	infrequently
drowsiness	–	often
insomnia	–	often
dizziness	often	often
episodes of loss of consciousness	infrequently *	rarely
paresthesia	–	infrequently
stupor	–	infrequently
From the side of the visual organ
changes in light perception (phosphenes)	very often	–
blurred vision	often	–
blurred vision	infrequently *	rarely
xerophthalmia	–	very rarely
dry eye syndrome	–	infrequently
conjunctival irritation	–	infrequently
reduced tear production	–	rarely
diplopia	infrequently	–
conjunctivitis	–	rarely
Hearing disorders and labyrinthine disorders
systemic vertigo (vertigo)	infrequently	–
tinnitus	–	rarely
hearing impairment, hearing	loss-	very rarely
deafness	–	very rarely
From the heart
, bradycardia		is common, often
grade I AV block (ECG prolongation of the PQ interval)	common	–
grade I AV block	–	infrequent
ventricular extrasystoles	common	–
palpitations		uncommon
-supraventricular extrasystoles	uncommon	–
atrial fibrillation	common	–
grade II AV block	very rare	–
grade III AV block	very rare	–
SSS	very rare	–
heart failure	–	infrequently
cardiogenic shock	–	infrequently increased
frequency and severity of seizures in patients with angina	pectoris-	very rarely
cardiac arrhythmias	–	rarely
impaired myocardial conduction	–	rarely
chest pain	–	infrequently
Vascular disorders
uncontrolled blood pressure	often	–
hypotension (possibly due to bradycardia)	infrequently *	–
orthostatic hypotension (with syncope)	–	often
cold sensation of the extremities	–	often
Raynaud	‘s disease-	often
dry gangrene (in patients with severe vascular disorders of the extremities before treatment)	–	very rarely
intermittent claudication	–	infrequently
decreased blood pressure	–	infrequently
Respiratory, thoracic and mediastinal
disorders dyspnea	infrequently	–
bronchospasm (including in patients who do not have a history of bronchial obstructive syndrome)	–	infrequently
rhinitis	–	rarely
shortness of breath during exercise	–	often
Gastrointestinal
disorders nausea	infrequently	often
constipation	infrequently	often
diarrhea	infrequently	often
abdominal pain	infrequently *	often
vomiting	–	often
dry oral mucosa	–	rarely
dysgeusia	–	rarely
retroperitoneal fibrosis	–	very rarely
Liver and biliary tract
disorders hepatitis	–	very rare
liver function abnormalities-rare liver function
disorders-rare
Skin and subcutaneous tissue
disorders angioedema	infrequently*	–
skin rash	infrequently*	infrequently
dystrophic skin changes	–	infrequently
skin redness	infrequently*	–
pruritus	infrequently*	–
urticaria	infrequently *	Infrequently
hyperhidrosis	–	infrequently
alopecia	–	infrequently
photosensitization reactions	–	very rarely
psoriasis and skin psoriasis-like rashes	-infrequently
Musculoskeletal and connective tissue
disorders muscle spasms	infrequently	rarely
arthralgia	–	very rarely
muscle weakness	–	rarely
muscle cramps	–	infrequently
General
asthenia disorders (possibly due to bradycardia)	infrequently*	–
increased fatigue	infrequently*	very often
general malaise (possibly due to bradycardia)	rare*	–
edema	–	infrequent
weight gain	–	infrequent
Laboratory and instrumental data
increased plasma creatinine	infrequently	–
prolongation of the QT interval on the ECG	infrequently	–
increased activity of hepatic transaminases	–	rare
Reproductive and breast
disorders sexual dysfunction / impotence	–	rarely
libido disorders	–	often
Peyronie	‘s disease-	very rare

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

Individual adverse reactions

Changes in light perception (phosphenes) It was observed 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, such phenomena were provoked by a sharp change in the intensity of lighting. Phosphenes can also occur that have the appearance of an areola, break up the visual image into separate parts (stroboscopic and kaleidoscopic effects), manifest themselves in the form of bright color flashes or multiple images (retinal persistence). As a rule, symptoms appear during the first 2 months of treatment and then recur. The expression of phosphenes is usually mild or moderate.All symptoms stopped during or after the end of treatment, and 77.5% of patients had symptoms that disappeared during the treatment period. Less than 1% of patients were forced to change their daily routine or stop treatment with the drug due to the occurrence of phosphenes in them.

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

According to a clinical study, atrial fibrillation was observed in 5.3% of patients taking ivabradine, compared with 3.8% in the placebo group. According to an analysis of combined data from clinical trials 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 taking ivabradine, compared with 4.08% in the control groups.

Interaction

In studies of the interaction between ivabradine and metoprolol in healthy volunteers, there was no mutual influence on the effects of each of the active substances. Information about possible interactions with other medications is provided below.

Contraindications to simultaneous use

Related to ivabradine

Concomitant use of ivabradine with potent inhibitors of the CYP3A4 isoenzyme, such as azole antifungal agents (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, oral erythromycin, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone, is contraindicated (see section “Contraindications”). Potent inhibitors of the CYP3A4 isoenzyme-ketoconazole (200 mg 1 time / day) or josamycin (1 g 2 times/day) increases the average concentration of ivabradine in blood plasma by 7-8 times.

Related to Metoprolol

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

Related to ivabradine and metoprolol

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

Slow calcium channel blockers (BCCs), such as verapamil or diltiazem, when administered intravenously can enhance the hypotensive effect of beta-blockers, exacerbating the effect on heart rate, AV conduction and myocardial contractility. It is possible to increase the negative inotropic and chronotropic effects. In this regard, during treatment with beta-blockers, intravenous use of BMCC is contraindicated (see the section “Contraindications”).

Undesirable drug combinations

Related to ivabradine

Medications that extend the QT interval

• Antiarrhythmic drugs that prolong the QT interval (for example, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).
• Medications that prolong the QT interval that are not antiarrhythmic (for example, pimozide, ziprasidone, sertindol, mefloquine, halofantrine, pentamidine, cisapride, erythromycin for intravenous use).

Concomitant use of ivabradine and these drugs should be avoided, as a decrease in heart rate may cause additional prolongation of the QT interval. If it is necessary to co-prescribe these drugs, the ECG values should be carefully monitored (see the section “Special instructions”).

Grapefruit juice: while taking grapefruit juice, there was a 2-fold increase in the concentration of ivabradine in the blood. During therapy with the drug, if possible, avoid the use of grapefruit juice.

Related to Metoprolol

Use of the following combinations with metoprolol should be excluded

Barbiturates: When phenobarbital is co-administered, barbiturates have been shown to significantly enhance metoprolol metabolism by inducing the enzyme. A decrease in the plasma concentration of metoprolol and, as a consequence, a decrease in its therapeutic effect (more active hepatic metabolism) was noted against the background of the use of phenobarbital.

Antihypertensive agents of central action (for example, clonidine): a significant increase in blood pressure is possible with sudden withdrawal of central-acting drugs. Do not abruptly stop taking antihypertensive drugs of central action. Sudden withdrawal of such drugs, especially if it precedes the withdrawal of a beta-blocker, may increase the risk of “withdrawal syndrome”.

Concomitant use of clonidine and non-selective beta-blockers, possibly also selective beta-blockers, increases the risk of “withdrawal syndrome”. In the case of concomitant use of clonidine, it should be continued for some time if the beta-blocker is discontinued.

Class I antiarrhythmic drugs (for example, quinidine, tocainide, procainamide, aimalin, amiodarone, flecainide, and disopyramide).

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

Concomitant use with caution

Related to ivabradine

Non-potassium-sparing diuretics (thiazide and loop diuretics): hypokalemia can increase the risk of developing arrhythmias. Due to the fact that ivabradine can cause bradycardia, the combination of hypokalemia and bradycardia may predispose to the development of severe cardiac arrhythmias, especially in patients with long QT syndrome, regardless of whether the prolongation of the QT interval is congenital or a consequence of drug exposure.

Moderate inhibitors of the CYP3A4 isoenzyme: ivabradine can be used in combination with other moderate inhibitors of the CYP3A4 isoenzyme (for example, fluconazole) if the minimum dose of ivabradine 2.5 mg 2 times/day is prescribed to patients with a resting heart rate of more than 70 beats/min, under heart rate control.

Inducers of the CYP3A4 isoenzyme (for example, such as rifampicin, barbiturates, phenytoin and St. John’s wort) when used together may lead to a decrease in the blood concentration and activity of ivabradine and require an increase in the dose of ivabradine. With the combined use of ivabradine 10 mg 2 times / day and preparations containing St. John’s wort, a twofold decrease in the AUC of ivabradine was noted. Do not use drugs containing St. John’s wort holed, against the background of ivabradine therapy.

Related to Metoprolol

Metoprolol is a substrate of the cytochrome P 450 isoenzyme CYP2D6. Substances that induce and inhibit enzymes can change the concentration of metoprolol in blood plasma.

Rifampicin reduces the concentration of metoprolol in the blood plasma.

Cimetidine, drugs containing ethanol, hydralazine may increase the concentration of metoprolol in blood plasma. Metoprolol is metabolized mainly in the liver, but not only with the participation of the 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, antipsychotic drugs (for example, chlorpromazine, triflupromazine, Chlorprothixen) and possibly propafenone, may increase the concentration of metoprolol in the blood. blood plasma.

The inhibitory effect of the CYP2D6 isoenzyme was also observed in amiodarone and quinidine (antiarrhythmic drugs).

Metoprolol may reduce the elimination of other medications (such as lidocaine).

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

It may be necessary to reduce the dose of metoprolol if you start taking the following groups of drugs::

• Nitrates – due to the risk of increasing the hypotensive effect of metoprolol;
• Cardiac Glycosides (digoxin) – when taken concomitantly with beta-blockers, they can slow down the rate of AV conduction and cause bradycardia;
• Beta-blockers (for example, eye drops) and MAO inhibitors-careful monitoring of the patient’s condition is recommended – since when taken simultaneously with beta-blockers, the risk of bradycardia and increased hypotensive effect increases;
• Adrenaline rush: if, under certain circumstances, patients receiving beta-blockers need epinephrine use, it should be borne in mind that the hypotensive effect is significantly less pronounced in cardioselective beta-blockers than in non-selective ones. ;

– Parasympathomimetics: concomitant use of parasympathomimetics may cause prolonged bradycardia;

– NSAIDs: concomitant use of NSAIDs, such as indomethacin, may reduce the antihypertensive effect of metoprolol;

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

Drug combinations to take into account

Related to ivabradine

There was no clinically significant effect on the pharmacodynamics and pharmacokinetics of ivabradine with the simultaneous use of the following drugs: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG-CoA reductase inhibitors (simvastatin), dihydropyridine derivatives of BMCC (amlodipine, lacidipine), digoxin and warfarin. Ivabradine has not been shown to have a 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 studies, no changes in the safety profile were observed when ivabradine was used with: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, beta-blockers, diuretics, aldosterone antagonists, short-and long-acting nitrates, HMG-CoA reductase inhibitors, fibrates, proton pump inhibitors, hypoglycemic agents for oral use, acetylsalicylic acid and other antiplatelet agents.

Cytochrome P 4503 A 4 (isoenzyme CYP3 A 4): ivabradine is metabolized in the liver with the participation of the CYP3A4 isoenzyme and is a very weak inhibitor of this cytochrome. Ivabradine does not significantly affect the metabolism and plasma concentrations of other substrates (potent, moderate and weak inhibitors) of the CYP3A4 isoenzyme. At the same time, inhibitors and inducers of the CYP3A4 isoenzyme can interact with ivabradine and have a clinically significant effect on its metabolism and pharmacokinetic properties. It was found that inhibitors of the CYP3A4 isoenzyme increase, and inducers of the CYP3A4 isoenzyme reduce the concentration of ivabradine in blood plasma. Increased plasma concentrations of ivabradine may increase the risk of severe bradycardia (see section “Special instructions”).

Related to Metoprolol

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

Concomitant use of mefloquine may be associated with the risk of severe bradycardia (additive effect).

Simultaneous intravenous use of dipyridamole may increase the antihypertensive effect.

Alpha-blockers 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).

Floctafenin: beta-blockers may interfere with the compensatory response of the cardiovascular system associated with hypotension or shock, which may develop against the background of floctafenin.

Antacids – with simultaneous use, an increase in the concentration of metoprolol in blood plasma was noted.

For children

Related to ivabradine

Interaction studies have been studied only in adults.

How to take, course of use and dosage

Implikor® should be taken orally 1 tablet 2 times / day, morning and evening, with meals, with a sufficient amount of liquid. The concentration of metoprolol in blood plasma increases when taken simultaneously with food (see the section “Pharmacokinetics”). This fact should be taken into account in the treatment of patients who took metoprolol on an empty stomach before prescribing the drug Implikor®.

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

If necessary, dose adjustment should be carried out with monopreparations of ivabradine and metoprolol.

The decision to change the dosage regimen is recommended based on a number of examinations, including heart rate, ECG or results of 24-hour Holter monitoring, as well as on the condition that the patient consistently receives the optimal dose of metoprolol and ivabradine.

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

If during treatment the resting heart rate decreases below 50 beats / min or the patient develops symptoms characteristic of bradycardia (dizziness, fatigue, or a decrease in blood pressure), the dose of the drug should be reduced by selecting a new dose for drugs based on monocomponents in order to ensure the optimal dose of metoprolol. After reducing the dose of ivabradine and metoprolol monocomponents, it is necessary to monitor the heart rate (see the section “Special instructions”). Treatment should be discontinued if, despite the dose reduction, heart rate remains below 50 beats / min or symptoms of bradycardia persist.

Patients with renal insufficiency with creatinine clearance greater than 15 ml/min do not need to change the dose of Implicor®. When lowering the price Creatinine clearance less than 15 ml / min should be used with caution.

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

In elderly patients over 65 years of age, Implicor®should be used with caution (see the section ” Contraindications “subsection”With caution”).

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

Overdose

No cases of overdose of Implicor®have been reported.

Symptoms associated with ivabradine may include severe and prolonged bradycardia.

Symptoms associated with metoprolol: there may be a marked decrease in blood pressure, sinus bradycardia, AV block, 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 medications, quinidine-containing medications, and barbiturates.

Symptoms of overdose may appear 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 charcoal), patients should be monitored in the ICU, where vital signs are corrected, if necessary.

In the case of severe bradycardia, symptomatic therapy is indicated. With bradycardia with impaired hemodynamics, intravenous use of beta-adrenomimetics, for example, isoprenaline, is performed. If necessary, a temporary artificial pacemaker may be implanted. A potential antidote for metoprolol is atropine (at a dose of 0.5-2 mg iv), its use is preceded by intravenous use of glucagon (1-5 mg, but not more than 10 mg). Additionally, it is possible to administer sympathomimetics in doses calculated for the patient’s body weight and taking into account the desired clinical effect (dobutamine, epinephrine). Higher than therapeutic doses may be required.

For convulsions, slow intravenous use of diazepam is recommended.

Special instructions

Patients with moderate hepatic insufficiency

In patients with moderate hepatic insufficiency (less than 9 points on the Child-Pugh scale), therapy with Implicor® should be carried out with caution.

Insufficient positive effect on clinical outcomes in patients with stable angina pectoris

Implicor® is indicated only as a symptomatic treatment for stable angina pectoris, since ivabradine does not have a positive effect on the frequency of cardiovascular events (for example, myocardial infarction or death due to cardiovascular causes). in patients with angina pectoris.

Heart rate monitoring

Given the significant variability of heart rate during the day, the determination of resting heart rate in patients taking ivabradine, when deciding on dose adjustment, should be performed using one of the following methods: serial heart rate measurement, ECG or 24-hour outpatient ECG monitoring. Such a determination should also be made in patients with low heart rate, in particular if the heart rate falls below 50 beats / min, or when the dose is reduced (see the section “Dosage regimen”).

Cardiac arrhythmias

Ivabradine is not effective for the treatment or prevention of arrhythmias, and it is likely that its effectiveness decreases with the development of tachyarrhythmias (for example, ventricular or supraventricular tachycardia). Therefore, the drug Implikor® It is not recommended for 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 were taking amiodarone or Class I antiarrhythmic drugs simultaneously with ivabradine.When using Implicor®, regular clinical monitoring of patients is necessary for the timely detection of atrial fibrillation (paroxysmal or permanent). In case of clinical indications (for example, worsening of angina pectoris, palpitation, irregular heart rate), an ECG should be included in the monitoring methods. Patients should be informed about the signs and symptoms of atrial fibrillation, and if such symptoms occur, they should be advised to contact their doctor immediately. If atrial fibrillation occurs during treatment, the ratio of expected benefit to possible risk with further use of ivabradine should be carefully analyzed again.

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

Use in patients with low heart rate

Implicor® is contraindicated if the resting heart rate is less than 70 beats/min before starting therapy.

If there is a persistent decrease in resting heart rate of less than 50 beats/min during Implicor therapy, or the patient develops symptoms associated with bradycardia (such as dizziness, fatigue, or hypotension), it is necessary to reduce the dose of the drug by switching to monocomponent medications until the optimal dose of metoprolol is reached, or discontinue treatment.

Combined use with slow calcium channel blockers (BMCC)

The use of the drug in combination with BMCC, reducing heart rate, such as verapamil or diltiazem, is contraindicated.

There was no change in the safety profile when ivabradine was used in combination with nitrates and BMCC dihydropyridine derivatives, such as amlodipine. No additional efficacy of ivabradine in combination with dihydropyridine BMCs has been established.

Chronic heart failure

During the use of Implikor® the condition of patients suffering from CHF should be stable. In patients with NYHA class IV CHF, Implicor® is recommended to be used with caution, as data on the use of the drug in this group of patients are limited.

Stroke

It is not recommended to prescribe Implicor immediately after a stroke, as there are no data on the use of the drug in these patients.

AV blockage of the first degree

In patients with grade I AV block, Implicor® therapy should be performed with caution.

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

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

Visual perception functions

Ivabradi affects the function of the retina of the eye. Currently, no toxic effects of ivabradine on the retina have been detected with prolonged use. If unexpected visual impairments occur, discontinuation of Implicor should be considered. Patients with retinitis pigmentosa should be treated with caution.

Discontinuation of therapy

Beta-blockers should not be abruptly discontinued, especially in patients with CHD. Discontinuation of Implicor® should be accompanied by concomitant use of metoprolol as a monocomponent drug at the optimal dose for the patient. Ivabradine can be stopped abruptly. The metoprolol dose should be reduced gradually, preferably for at least 2 weeks, while starting replacement therapy if necessary. If the patient develops any symptoms, the dose reduction should be more gradual.

Arterial hypotension

Due to insufficient clinical data on the use of ivabradine in patients with mild to moderate hypotension, Implicor® should be administered with caution in these patients. Implicor®is contraindicated in patients with severe arterial hypotension (systolic blood pressure less than 90 mm Hg and diastolic blood pressure less than 50 mm Hg).

Atrial fibrillation – cardiac arrhythmias

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

Use in patients with congenital long QT syndrome or in patients taking medications that prolong the QT interval

Implicor® it should not be used in patients with congenital long QT syndrome, or in combination with drugs that prolong the QT interval (see the section “Drug interaction”). If necessary, such therapy should be provided with constant cardiac monitoring. A decrease in heart rate caused by ivabradine can exacerbate the prolongation of the QT interval, which, in turn, can serve as a trigger for severe cardiac arrhythmias, including ventricular tachycardia of the “pirouette” type.

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

There is evidence that 7.1% of patients treated with ivabradine experienced episodes of elevated blood pressure compared to 6.1% of patients treated with placebo. These episodes were observed, as a rule, shortly after the change in antihypertensive therapy, were of a short-term nature and did not significantly affect the effect of ivabradine. In patients with chronic heart failure receiving ivabradine, the change in therapy should be accompanied by regular monitoring of blood pressure.

Use in patients with bronchial asthma and COPD

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

If necessary, bronchodilators that selectively stimulate beta_-2-adrenergic receptors, such as terbutaline, should be prescribed. If the group of selective beta_-2-adrenomimetics is already used, it may be necessary to increase their dose.

Severe peripheral vascular lesions

In patients with peripheral artery disease (Raynaud’s disease or syndrome, arteritis, or chronic vascular diseases of the lower extremities), the use of beta-blockers may worsen the course of the disease. In such cases, you should discontinue Implicor® and select individual doses of monocomponent drugs. Cardioselective beta-blockers with partial agonistic activity are preferred, but they should also be used with caution.

Pheochromocytoma

If a pheochromocytoma diagnosis is confirmed or suspected, 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 on the background of insulin therapy or treatment with oral hypoglycemic drugs. Patients should be warned that beta-blockers may 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.

Prinzmetal angina pectoris

The use of beta-blockers may increase the duration and frequency of Prinzmetal angina attacks. The use of cardioselective beta_-1-blockers 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 a history of psoriasis should be given beta-blockers only after careful assessment of the benefit-risk ratio.

Thyrotoxicosis

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

General anesthesia

Long-term treatment with beta-blockers, as a rule, should not be canceled before surgery. Reduced ability of the myocardium to respond to adrenergic stimulation may increase the risk of complications of general anesthesia and surgical procedures. The anesthesiologist should be warned about the treatment being performed. If the withdrawal of the beta-blocker is still necessary, the drug is stopped gradually. The drug should be completely 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, since an excessive decrease in blood pressure or heart rate can lead to insufficient blood supply to vital organs during treatment with beta-blockers.

Allergic reactions

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

Metoprolol may increase sensitivity to allergens and increase the severity of anaphylactic reactions. The use of epinephrine to patients receiving beta-blockers is not always accompanied by the desired therapeutic effect (see the section “Drug interaction”).

For athletes

It is necessary to take into account the possibility of obtaining positive results of a doping test in athletes when using Implikor®, which contains metoprolol.

Influence on the ability to drive vehicles and mechanisms

Available data for monocomponents suggest a possible effect of the drug Implikor® on the ability to drive vehicles and work with mechanisms.

Ivabradine may have an adverse effect on the ability to drive a car. Patients should be warned that ivabradine may 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 triggered by a sharp change in light intensity, especially when traveling at night. Ivabradine does not affect the work with mechanisms. In the post-marketing period, there were reports of driving difficulties due to visual symptoms while taking ivabradine.

Metoprolol affects the ability to drive vehicles and work with mechanisms. Patients should be warned about possible undesirable symptoms (such as headache, dizziness, increased fatigue). In addition, these clinical symptoms may worsen with alcohol intake or changes in therapy. If the above symptoms occur, patients should refrain from performing activities that require concentration of attention and a high rate of psychomotor reactions.

Storage conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C.

Shelf life

3 years

Active ingredient

Ivabradine, Metoprolol

Conditions of release from pharmacies

By prescription

Dosage form

Tablets