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.