IMPLICOR Metoprolol Tartrate / Ivabradine 25mg / 5mg Tablet 1's

Symptomatic treatment of chronic stable angina pectoris as substitution therapy in adult patients with normal sinus rhythm already controlled by metoprolol and ivabradine taken concomitantly at the same dose level.

 

The recommended dose of Metoprolol tartrate + Ivabradine (Implicor) is one tablet twice daily, once in the morning and once in the evening.
This medicine should only be used in patients controlled on stable doses of the monocomponents given concurrently when metoprolol is at the optimal dose.
It is recommended that the decision to titrate treatment takes place with the availability of serial heart measurements, ECG or ambulatory 24-hour monitoring and titration should be done with the individual components metoprolol and ivabradine, ensuring the patient is maintained at an optimal dose of metoprolol and ivabradine. If during treatment, heart rate decreases below 50 beats per minute at rest or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, down titration should be done with the individual monocomponents metoprolol and ivabradine, ensuring the patient is maintained at an optimal dose of metoprolol. After dose reduction, heart rate should be monitored.
Treatment must be discontinued if heart rate remains below 50 bpm or symptoms of bradycardia persist despite dose reduction.
Patients with renal impairment: No dosage adjustment is required in patients with renal insufficiency and creatinine clearance above 15 mL/min.
This medicine should be used with precaution in patients with creatinine clearance below 15 mL/min.
Patients with hepatic impairment: Metoprolol tartrate + Ivabradine (Implicor) can be administered in patients with mild hepatic impairment.
Caution should be exercised when administering in patients with moderate hepatic impairment.
This medicine is contraindicated in patients with severe hepatic impairment.
Older people: Metoprolol tartrate + Ivabradine (Implicor) can be administered in elderly patients with caution.
Pediatric population: The safety and efficacy of this medicine in children and adolescents have not been established. No data are available.
Method of administration: Metoprolol tartrate + Ivabradine (Implicor) should be taken orally twice daily during meals. The exposure of metoprolol is increased when administered with food. This should be considered in patients who currently take metoprolol in a fasting state and switch to Metoprolol tartrate + Ivabradine (Implicor).

 

Overdosage

Should be taken with food.

Hypersensitivity to the active substances or to any of the excipients or to other beta-blockers (cross sensitivity between beta blockers may occur).
Symptomatic bradycardia.
Cardiogenic shock.
Sick sinus syndrome (including Sino-atrial block).
AV-block of 2nd and 3rd degree.
Acute myocardial infarction or patients with suspected acute myocardial infarction complicated by significant bradycardia, first degree heart block, systolic hypotension (less than 100 mmHg) and/or severe heart failure.
Severe (<90/50 mmHg) or symptomatic hypotension.
Unstable or acute heart failure.
Patients undergoing intermittent inotropic therapy with beta-receptor agonist.
Pacemaker dependent (heart rate imposed exclusively by the pacemaker).
Unstable angina.
Severe peripheral vascular disease.
Untreated pheochromocytoma.
Severe hepatic insufficiency.
Metabolic acidosis.
Combination with strong cytochrome P450 3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone.
Combination with verapamil or diltiazem which are moderate CYP3A4 inhibitors with heart rate reducing properties.
Pregnancy, lactation and women of child-bearing potential not using appropriate contraceptive measures.

Special warnings: Lack of benefit on clinical outcomes in patients with symptomatic chronic stable angina pectoris: Metoprolol tartrate + Ivabradine (Implicor) is indicated only for symptomatic treatment of chronic stable angina pectoris because ivabradine has no benefits on cardiovascular outcomes (e.g. myocardial infarction or cardiovascular death).
Measurement of heart rate: Given that the heart rate may fluctuate considerably over time, serial heart rate measurements, ECG or ambulatory 24-hour monitoring should be considered when determining resting heart rate in patients on treatment with ivabradine when titration is considered. This also applies to patients with a low heart rate, in particular when heart rate decreases below 50 bpm, or after dose reduction.
Cardiac arrhythmias: Ivabradine is not effective in the treatment or prevention of cardiac arrhythmias and likely loses its efficacy when a tachyarrhythmia occurs (e.g. ventricular or supraventricular tachycardia). Metoprolol tartrate + Ivabradine (Implicor) is therefore not recommended in patients with atrial fibrillation or other cardiac arrhythmias that interfere with sinus node function.
In patients treated with ivabradine the risk of developing atrial fibrillation is increased. Atrial fibrillation has been more common in patients using concomitantly amiodarone or potent class I anti-arrhythmics. It is recommended to regularly clinically monitor Metoprolol tartrate + Ivabradine (Implicor) treated patients for the occurrence of atrial fibrillation (sustained or paroxysmal), which should also include ECG monitoring if clinically indicated (e.g. in case of exacerbated angina, palpitations, irregular pulse). Patients should be informed of signs and symptoms of atrial fibrillation and be advised to contact their physician if these occur.
If atrial fibrillation develops during treatment, the balance of benefits and risks of continued ivabradine treatment should be carefully reconsidered.
Chronic heart failure patients with intraventricular conduction defects (bundle branch block left, bundle branch block right) and ventricular dyssynchrony should be monitored closely.
Use in patients with a low heart rate: Ivabradine must not be initiated in patients with a pre-treatment resting heart rate below 70 beats per minutes.
If, during treatment with Metoprolol tartrate + Ivabradine (Implicor), resting heart rate decreases persistently below 50 bpm or the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension, down titration should be done with the individual monocomponents ensuring the patient is maintained at an optimal dose of metoprolol or treatment discontinued.
Combination with calcium channel blockers: Concomitant use of Metoprolol tartrate + Ivabradine (Implicor) with heart rate reducing calcium channel blockers such as verapamil or diltiazem is contraindicated. No safety issue has been raised on the combination of ivabradine with nitrates and dihydropyridine calcium channel blockers such as amlodipine. Additional efficacy of ivabradine in combination with dihydropyridine calcium channel blockers has not been established.
Chronic heart failure: Heart failure must be stable before considering ivabradine treatment. Metoprolol tartrate + Ivabradine (Implicor) should be used with caution in heart failure patients with NYHA functional classification IV due to limited amount of data in this population.
Stroke: The use of Metoprolol tartrate + Ivabradine (Implicor) is not recommended immediately after a stroke since no data is available in these situations with ivabradine.
Visual function: Ivabradine influences on retinal function. To date, there is no evidence of a toxic effect of ivabradine on the retina, but the effects of long-term ivabradine treatment beyond one year on retinal function are currently not known. Cessation of Metoprolol tartrate + ivabradine (Implicor) should be considered if any unexpected deterioration in visual function occurs. Caution should be exercised in patients with retinitis pigmentosa.
Precautions for Use: Stopping treatment: Abrupt cessation of therapy with a beta-blocker should be avoided, especially in patients with ischemic heart disease. The cessation of the therapy should immediately be followed by the intake of metoprolol mono-component ensuring the patient is maintained at an optimal dose of metoprolol. Ivabradine intake can be interrupted if necessary. Posology of metoprolol mono-component should be decreased gradually; ideally over a period of at least two weeks while at the same time starting the replacement therapy if necessary. If the patient develops any symptoms the dose should be reduced more slowly.
Patients with hypotension: Limited data are available in patients with mild to moderate hypotension treated with ivabradine, and Metoprolol tartrate + Ivabradine (Implicor) should therefore be used with caution in these patients. This medicine is contraindicated in patients with severe hypotension (blood pressure <90/50 mmHg).
Atrial fibrillation - Cardiac arrhythmias: There is no evidence of risk of (excessive) bradycardia on return to sinus rhythm when pharmacological cardioversion is initiated in patients treated with ivabradine. However, in the absence of extensive data, non urgent DC-cardioversion should be considered 24 hours after the last dose of ivabradine.
Use in patients with congenital QT-syndrome or treated with QT prolonging medicinal products: The use of Metoprolol tartrate + Ivabradine (Implicor) in patients with congenital QT syndrome or treated with QT prolonging medicinal products should be avoided. If the combination appears necessary, close cardiac monitoring is needed.
Heart rate reduction, as caused by ivabradine, may exacerbate QT prolongation, which may give rise to severe arrhythmias, in particular Torsade de pointes.
Hypertensive patients requiring blood pressure treatment modifications: In the SHIFT trial, more patients experienced episodes of increased blood pressure while treated with ivabradine (7.1%) compared to patients treated with placebo (6.1%). These episodes occurred most frequently shortly after blood pressure treatment was modified, were transient, and did not affect the treatment effect on ivabradine. When treatment modifications are made in chronic heart failure patients treated with ivabradine blood pressure should be monitored at an appropriate interval.
Bronchial asthma and chronic obstructive pulmonary diseases: Although metoprolol is a cardioselective betablocker, caution is advised in patients with bronchial asthma and chronic obstructive pulmonary diseases. If necessary, simultaneously bronchodilator drugs, that selectively stimulate the β2-receptors, for example, such as terbutaline, are prescribed. If the patient is already using a β2-receptor stimulant, it may sometimes be necessary to adjust the dosage.
Severe peripheral arterial disease: In patients suffering from peripheral arterial disorders (Raynaud's disease or syndrome, arteritis or chronic occlusive arterial disease of the lower limbs), beta-blockers can aggravate the condition. In these cases, stop treatment with Metoprolol tartrate + Ivabradine (Implicor) and titrate with the individual monocomponents. A cardioselective beta-blocker with partial agonist activity is preferable and should be administered with caution.
Pheochromocytoma: When known or suspected to have pheochromocytoma, beta-blockers should always be given in combination with an alpha blocker.
Diabetic patients: Caution is advised when Metoprolol tartrate + Ivabradine (Implicor) is used in patients with diabetes mellitus, especially those who are using insulin or oral antidiabetic drugs. It is recommended to inform diabetic patients that beta-blockers may mask the hypoglycemic tachycardia; however, other signs of hypoglycemia such as drowsiness and sweating may not necessarily be suppressed and increased sweating may occur.
Prinzmetal angina: Beta-blockers may increase the number and duration of attacks in patients with Prinzmetal angina. The use of a cardioselective beta-1 blocker is possible in minor and associated forms, provided it is administered with a vasodilator.
Psoriasis: Exacerbation of psoriasis has been reported with beta-blockers. Patients with psoriasis or with a history of psoriasis should only be given beta-blockers after carefully balancing the benefits against the risks.
Thyrotoxicosis: Beta-blockers can mask the symptoms of thyrotoxicosis.
General anesthesia: Long-term treatment with beta-blockers should not be routinely withdrawn prior to major surgery. The reduced ability of the heart to respond to adrenergic stimulation can increase the risks of general anesthesia and surgical procedures. Before any surgery requiring general anesthesia, the anesthetist should be informed that the patient is being treated with a beta-blocker. If it is thought necessary to withdraw the beta-blocker before surgery, this should be done gradually and completed about 48 hours before general anesthesia.
Older people: Elderly patients must be closely monitored since an excessive decrease in blood pressure or heart rate may lead to an insufficient blood supply to vital organs with beta-blockers.
Allergic reactions: Caution is advised in patients with a history of severe hypersensitivity reactions and patients undergoing desensitization therapy as there is a risk of more severe anaphylactic reactions.
Metoprolol can increase the sensitivity to allergens and the severity of anaphylactic reactions. Therapy with adrenaline does not always have the desired therapeutic effect in individual patients treated with beta-receptor blockers.
Effects on ability to drive and use machines: Based on existing data with the monocomponents the use of Metoprolol tartrate + Ivabradine (Implicor) may affect the ability to drive or use machinery.
Ivabradine may affect the patient's ability to drive. Patients should be warned that ivabradine may cause transient luminous phenomena (consisting mainly of phosphenes). Luminous phenomena may occur in situations when there are sudden variations in light intensity, especially when driving at night. Ivabradine has no influence on the ability to use machines. However, in post-marketing experience, cases of impaired driving ability due to visual symptoms have been reported.
Metoprolol may affect patients' ability to drive and operate machinery. Patients should be warned that headaches, dizziness or fatigue may occur. These effects may possibly be enhanced in the case of concomitant ingestion of alcohol or after changing to another medicinal product.

 

Use In Pregnancy & Lactation

The safety profile of Metoprolol tartrate + Ivabradine (Implicor) presented as follows is based on the known safety profile of the individual components.
Summary of the profile: The most common adverse reactions with ivabradine is luminous phenomena (phosphenes) and bradycardia are dose dependent and related to the pharmacological effect of the medicinal product. The most commonly reported adverse reactions with metoprolol are bradycardia, nightmares, headache, somnolence, insomnia, dizziness, palpitations, orthostatic hypotension, peripheral coldness, Raynaud's disease, dyspnea exertional, nausea, constipation, diarrhea, abdominal pain, vomiting, fatigue and libido disorder.
Tabulated list of adverse reactions: The following undesirable effects have been observed during treatment with ivabradine and metoprolol given separately and ranked under the MedRA classification by body system, and under heading of frequency using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See Tables A and B.)

Description of selected adverse reactions: Luminous phenomena (phosphenes) were reported by 14.5% of patients, described as a transient enhanced brightness in a limited area of the visual field. They are usually triggered by sudden variations in light intensity. Phosphenes may also be described as a halo, image decomposition (stroboscopic or kaleidoscopic effects), colored bright lights, or multiple images (retinal persistency). The onset of phosphenes is generally within the first two months of treatment after which they may occur repeatedly. Phosphenes were generally reported to be of mild to moderate intensity. All phosphenes resolved during or after treatment, of which a majority (77.5%) resolved during treatment. Fewer than 1% of patients changed their daily routine or discontinued the treatment in relation with phosphenes.
Bradycardia was reported by 3.3% of patients particularly within the first 2 to 3 months of treatment initiation. 0.5% of patients experienced a severe bradycardia below or equal to 40 bpm.
In the SIGNIFY study, atrial fibrillation was observed in 5.3% of patients taking ivabradine compared to 3.8% in the placebo group. In a pooled analysis of all the Phase II/III double blind controlled clinical trials with a duration of at least 3 months including more than 40,000 patients, the incidence of atrial fibrillation was 4.86% in ivabradine treated patients compared to 4.08% in controls, corresponding to a hazard ratio of 1.26, 95% CI [1.15-1.39].

 

No interactions between metoprolol and ivabradine have been observed in an interaction study conducted in healthy volunteers. Information on interactions with other products that are known for the individual active substances is provided below.
Contraindication of concomitant use: Linked to ivabradine: The concomitant use of potent CYP3A4 inhibitors such as azole antifungals (ketoconazole, itraconazole), macrolide antibiotics (clarithromycin, erythromycin per os, josamycin, telithromycin), HIV protease inhibitors (nelfinavir, ritonavir) and nefazodone is contra-indicated. The potent CYP3A4 inhibitors ketoconazole (200 mg once daily) and josamycin (1 g twice daily) increased ivabradine mean plasma exposure by 7 to 8 fold.
Linked to ivabradine and metoprolol: Moderate CYP3A4 inhibitors: specific interaction studies in healthy volunteers and patients have shown that the combination of ivabradine with the heart rate reducing agents diltiazem or verapamil resulted in an increase in ivabradine exposure (2 to 3 fold increase in AUC) and an additional heart rate reduction of 5 bpm. The concomitant use of ivabradine with these medicinal products is contraindicated.
Calcium channel blockers such as Verapamil or Diltiazem administered intravenously may enhance the depressant effect of beta-blockers on blood pressure, heart rate, myocardial contractility and atrioventricular conduction. An increase in negative inotropic and chronotropic effects can occur, therefore these medicinal products should not be administered intravenously to patients who are being treated with beta blockers.
Concomitant use not recommended: Linked to ivabradine: QT prolonging medicinal products: Cardiovascular QT prolonging medicinal products (e.g. quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone).
Non cardiovascular QT prolonging medicinal products (e.g. pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous erythromycin).
The concomitant use of cardiovascular and non cardiovascular QT prolonging medicinal products with ivabradine should be avoided since QT prolongation may be exacerbated by heart rate reduction. If the combination appears necessary, close cardiac monitoring is needed.
Grapefruit juice: ivabradine exposure was increased by 2-fold following the co-administration with grapefruit juice. Therefore, the intake of grapefruit juice should be avoided.
Linked to metoprolol: The following combinations with metoprolol should be avoided: Barbituric acid derivatives: Barbiturates (studied for pentobarbital) induce the metabolism of metoprolol through enzyme induction. Decreased plasma concentrations of metoprolol with decreased clinical effects (faster hepatic metabolism) has been observed with phenobarbital.
Centrally acting antihypertensive agents (e.g. clonidine).
Significant increase in blood pressure may occur if treatment with the centrally acting antihypertensive agent is stopped suddenly. Avoid stopping the centrally acting antihypertensive agent abruptly. Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase risk of "rebound hypertension".
The concomitant use of clonidine with a non-selective beta blocker, and possibly also with a selective beta blocker, increases the risk of rebound hypertension. If clonidine is administered concomitantly, the administration of the clonidine medication needs to be continued for some time after beta-blocker therapy is discontinued.
Class 1 antiarrhythmic agents (e.g. quinidine, tocainide, procainamide, aimaline, amiodarone, flecainide and disopyramide).
Beta-blockers may increase the negative inotropic effect of antiarrhythmic drugs and their effect on atrial conduction time. In particular, in patients with pre-existing sinus node dysfunction, concomitant administration of amiodarone may cause additional electrophysiological effects including bradycardia, sinus arrest and atrioventricular block. Amiodarone has an extremely long half-life (approximately 50 days), which means that interactions can occur a long time after discontinuation of the preparation. Antiarrhythmics such as quinidine, tocainide, procainamide, aimaline, amiodarone, flecainide and disopyramide may potentiate the effect of metoprolol on heart rate and atrioventricular conduction.
Concomitant use with precaution: Linked to ivabradine: Potassium-depleting diuretics (thiazide diuretics and loop diuretics): Hypokalemia can increase the risk of arrhythmia. As ivabradine may cause bradycardia, the resulting combination of hypokalemia and bradycardia is a predisposing factor to the onset of severe arrhythmias, especially in patients with long QT syndrome, whether congenital or substance-induced.
Moderate CYP3A4 inhibitors: the concomitant use of ivabradine with other moderate CYP3A4 inhibitors (e.g. fluconazole) may be considered at the starting dose of 2.5 mg twice daily and if resting heart rate is above 70 bpm, with monitoring of heart rate.
CYP3A4 inducers: CYP3A4 inducers (e.g. rifampicin, barbiturates, phenytoin, Hypericum perforatum [St. John's Wort]) may decrease ivabradine exposure and activity. The concomitant use of CYP3A4 inducing medicinal products may require an adjustment of the dose of ivabradine. The combination of ivabradine 10 mg twice daily with St. John's Wort was shown to reduce ivabradine AUC by half. The intake of St. John's Wort should be restricted during the treatment with ivabradine.
Linked to metoprolol: Metoprolol serves as a substrate for CYP2D6, a cytochrome P 450 isoenzyme.
Enzyme inducing and enzyme inhibiting substances can influence the plasma concentration of metoprolol.
Rifampicin lowers the plasma concentration of metoprolol.
Cimetidine, alcohol and hydralazine can increase the plasma concentration of metoprolol. Metoprolol is mainly, but not exclusively, metabolized via the hepatic enzyme cytochrome CYP 2D6.
Substances that have an inhibitory effect on CYP 2D6, as e.g. selective serotonin-reuptake inhibitors like paroxetine, fluoxetine and sertraline as well as diphenhydramine, hydroxychloroquine, celecoxib, terbinafine, neuroleptics (e.g. chlorpromazine, triflupromazine, chlorprothixene) and possibly propafenon can increase the plasma concentration of metoprolol.
An inhibitory effect on CYP 2D6 has also been reported for amiodarone and quinidine (antiarrhythmics).
Metoprolol can reduce the elimination of other medicinal products (e.g. lidocaine).
In patients using beta-receptor blockers the bradycardic effect is enhanced by inhalation anesthetics.
When initiating treatment with these medicinal products in patients treated with metoprolol, the dose of metoprolol may need to be reduced: Nitrates may enhance the hypotensive effect of metoprolol.
Digitalis glucosides (digoxin): Digitalis glycosides in combination with beta-receptor blockers may increase the atrioventricular conduction time and induce bradycardia.
Beta-receptor blockers (e.g. eye drops) or MAO-inhibitors: Patients concomitantly treated with metoprolol and other beta-receptor blockers (e.g. eye drops) or MAO-inhibitors should be closely monitored. Concomitant administration with beta-blockers may result in bradycardia and an enhanced hypotensive effect.
Adrenaline: if, under certain circumstances, adrenaline is administered to patients who take beta-receptor blockers, cardioselective beta-receptor blockers have a markedly lower impact on blood pressure control than non-selective beta-receptor blockers.
Parasympathomimetic drugs: The concomitant use of parasympathomimetics may cause long-term bradycardia.
Non-steroidal anti-inflammatory/antirheumatic agents (NSAIDs) The concomitant use of non-steroidal anti-inflammatory drugs such as indomethacin may reduce the ant hypertensive effect of metoprolol.
Insulin and oral antidiabetic agents: Metoprolol may increase their hypoglycemic effect and symptoms of hypoglycemia may be masked. In this case, the dosage of the oral blood glucose-reducing drug must be adjusted.
Combinations use to be taken into consideration: Linked to ivabradine: Specific drug-drug interaction studies have shown no clinically significant effect of the following medicinal products on pharmacokinetics and pharmacodynamics of ivabradine: proton pump inhibitors (omeprazole, lansoprazole), sildenafil, HMG CoA reductase inhibitors (simvastatin), dihydropyridine calcium channel blockers (amlodipine, lacidipine), digoxin and warfarin. In addition there was no clinically significant effect of ivabradine on the pharmacokinetics of simvastatin, amlodipine, lacidipine, on the pharmacokinetics and pharmacodynamics of digoxin, warfarin and on the pharmacodynamics of aspirin.
In pivotal phase III clinical trials the following medicinal products were routinely combined with ivabradine with no evidence of safety concerns: angiotensin converting enzyme inhibitors, angiotensin II antagonists, beta-blockers, diuretics, anti-aldosterone agents, short and long acting nitrates, HMG CoA reductase inhibitors, fibrates, proton pump inhibitors, oral antidiabetics, aspirin and other anti-platelet medicinal products.
Cytochrome P450 3A4 (CYP3A4): Ivabradine is metabolized by CYP3A4 only and it is a very weak inhibitor of this cytochrome. Ivabradine was shown not to influence the metabolism and plasma concentrations of other CYP3A4 substrates (mild, moderate and strong inhibitors). CYP3A4 inhibitors and inducers are liable to interact with ivabradine and influence its metabolism and pharmacokinetics to a clinically significant extent. Drug-drug interaction studies have established that CYP3A4 inhibitors increase ivabradine plasma concentrations, while inducers decrease them. Increased plasma concentrations of ivabradine may be associated with the risk of excessive bradycardia.
Linked to metoprolol: Tricyclic antidepressants and neuroleptics: Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).
Mefloquine: Risk of excessive bradycardia (additive bradycardiac effects).
Dipyridamole (IV): Increased antihypertensive effect.
Urology alpha-blockers (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): Increased hypotensive effect. Greater risk of orthostatic hypotension.
Ergotamine: Increase of the vasoconstrictive effect.
Skeletal muscle relaxant: Curare-type muscle relaxant (enhancement of the neuromusular block).
Floctafenine: Beta blockers may impede the compensatory cardiovascular reactions associated with hypotension or shock that may be induced by floctafenine.
Antacid: An increase in the plasma concentrations of metoprolol has been observed when the drug was co-administered with an antacid.
Pediatric population: Linked to ivabradine: Interaction studies have only been performed in adults.

Storage

Action

Anti-Anginal Drugs / Beta-Blockers