Implicor Special Precautions




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Full Prescribing Info
Special Precautions
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.
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