Implicor, 7.5 mg+25 mg 56 pcs

Pharmacotherapeutic group: Beta-adrenoblockers, other combinations.

ATX code: C07FX05.

Indications

Active ingredient

Composition

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 administered to patients who are already taking ivabradine and metoprolol at optimal doses.

If necessary, dose adjustment should be made with ivabradine and metoprolol monotherapies.

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

/p> 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. T1/2 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:

– 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 in making dose adjustments decisions. 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 dysfunction (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 sinus rhythm recovery after pharmacological cardioversion in patients taking ivabradine. However, due to insufficient data, electrically-guided planned cardioversion should not be performed earlier than 24 hours 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

Implicor

Contraindications

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 frequently (≥1/10); frequently (≥1/100 to <1/10), infrequently (≥1/1000 to <1/100), rarely (≥1/10 000 to <1/1000); very rarely (<1/10 000); frequency not specified (cannot be determined from available data).

* 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 due to the onset of 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.

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.