Logimax Drug Interactions

Concomitant administration of substances that influence the cytochrome P450 system can affect the plasma concentration of both felodipine and metoprolol. Felodipine and metoprolol do not interact with each other, since they utilize different isoenzymes of cytochrome P450.
Interactions with felodipine: Felodipine is a CYP3A4 substrate. Drugs that inhibit or induce CYP3A4 greatly affect the plasma concentration of felodipine.
Cytochrome P450 inducers: Drugs that increase the metabolism of felodipine through induction of cytochrome P450 are e.g. carbamazepine, phenytoin, phenobarbital and rifampicin, and also St. John's wort (Hypericum perforatum). In cases of concomitant administration of carbamazepine, phenytoin and phenobarbital the felodipine AUC fell by 93% and the Cmax by 82%. Combination with CYP3A4 inducers should be avoided.
Cytochrome P450 inhibitors: Drugs that are potent CYP3A4 inhibitors are e.g. azole antifungal agents, (itraconazole, ketoconazole), macrolide antibiotics (erythromycin) and HIV-protease inhibitors. During concomitant administration of itraconazole, the felodipine Cmax increased 8-fold and the AUC 6-fold. During concomitant administration of erythromycin, the felodipine Cmax and AUC increased approximately 2.5-fold. Combination with potent CYP3A4 inhibitors should be avoided.
Grapefruit juice inhibits CYP3A4. Administration of felodipine in combination with grapefruit juice increased the felodipine Cmax and AUC approximately 2-fold. Combination with grapefruit juice should be avoided.
Tacrolimus: Felodipine can cause increased concentrations of tacrolimus. In cases of concomitant use, the serum concentration of tacrolimus must be monitored, and the tacrolimus dose may need to be adjusted.
Cyclosporin: During concomitant treatment with cyclosporin and felodipine the Cmax of felodipine increased by 150% and the AUC by approx. 60%. In contrast, the effect of felodipine on the kinetics of cyclosporin is marginal.
Cimetidine: During concomitant treatment with cimetidine and felodipine the Cmax and AUC of felodipine were increased by approx. 55%.
Interactions with metoprolol: Metoprolol is a CYP2D6-substrate. Drugs that inhibit CYP2D6 can have an effect on the plasma concentration of metoprolol. Examples of drugs that inhibit CYP2D6 are quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine. When treatment with these drugs are initiated the dose of Felodipine/Metoprolol succinate (LOGIMAX) might have to be reduced for patients treated with Felodipine/Metoprolol succinate (LOGIMAX).
The following combinations with Felodipine/Metoprolol succinate (LOGIMAX) should be avoided: Barbituric acid derivatives: Barbiturates (studied for pentobarbital) induce the metabolism of metoprolol to a slight degree through enzyme induction.
Propafenone: When propafenone was started in four patients who were already receiving treatment with metoprolol, the plasma concentrations of metoprolol increased 2-5-fold, and two patients experienced typical metoprolol side effects. The interaction was confirmed in tests on eight healthy trial subjects. The interaction is probably due to the fact that propafenone, like quinidine, inhibits the metabolism of metoprolol via cytochrome P4502D6. The combination is thought to be difficult to manage since propafenone also has β-receptor-blocking properties.
Verapamil: In combination with β-receptor blockers (has been described for atenolol, propranolol and pindolol), verapamil can cause bradycardia and a fall in blood pressure. Verapamil and β-blockers have additive inhibitory effects on AV conduction and sinus node function.
The following combinations with Felodipine/Metoprolol succinate (LOGIMAX) may require a dose adjustment: Class I antiarrhythmic drugs: Class I antiarrhythmic drugs and β-receptor blockers have additive negative inotropic effects, which can result in serious hemodynamic side effects in patients with impaired left ventricular function. The combination should also be avoided in "sick sinus syndrome" and pathological AV conduction. The interaction is best documented for disopyramide.
Diphenhydramine: Diphenhydramine reduces (2.5-fold) clearance of metoprolol to alpha-hydroxymetoprolol in rapid hydroxylators via CYP2D6. At the same time, the effects of metoprolol are potentiated.
Clonidine: The hypertensive reaction in the event of sudden withdrawal of clonidine can be potentiated by β-blockers. If concomitant treatment with clonidine must be discontinued, the β-blocker must be withdrawn a few days before clonidine.
Diltiazem: Diltiazem and β-receptor blockers have additive inhibitory effects on AV conduction and sinus node function. Pronounced bradycardia has been observed (case reports) in cases of combination treatment with diltiazem.
Non-steroidal anti-inflammatory drugs (NSAIDs): Anti-inflammatory drugs of the NSAID type counteract the antihypertensive effect of β-receptor blockers. Indomethacin in particular has been studied. This interaction is thought not to occur with sulindac. In a study with diclofenac no such reaction could be detected.
Phenylpropanolamine: Phenylpropanolamine (norephedrine) in single doses of 50 mg can increase diastolic blood pressure to pathological values in healthy trial subjects. Propranolol generally counteracts the rise in blood pressure induced by phenylpropanolamine. However, β-receptor blockers can cause paradoxical hypertensive reactions in patients who take high doses of phenylpropanolamine. Hypertensive crises during treatment with phenylpropanolamine alone have been described in a few cases.
Epinephrine: There have been about ten reports of marked hypertension and bradycardia in patients on treatment with non-selective β-receptor blockers (incl. pindolol and propranolol) who were given epinephrine (adrenaline). These clinical observations have been confirmed in studies on healthy trial subjects. It has also been suggested that epinephrine as an additive to local anesthetics can cause these reactions on intravascular administration. The risk is thought to be considerably less with cardio-selective β-receptor blockers.
Quinidine: Quinidine inhibits the metabolism of metoprolol in so-called rapid hydroxylators (approx. 90% in Sweden), resulting in greatly increased plasma levels and increased β-blockade. Corresponding interactions are thought to occur with other β-blockers that are metabolized by the same enzyme (cytochrome P4502D6).
Amiodarone: One case report suggests that patients treated with amiodarone may develop pronounced sinus bradycardia if they are treated concomitantly with metoprolol. Amiodarone has an extremely long half-life (approx. 50 days), which means that interactions can occur a long time after the preparation has been withdrawn.
Rifampicin: Rifampicin can induce the metabolism of metoprolol, resulting in reduced plasma levels.
Patients receiving concomitant treatment with metoprolol and other β-receptor blockers (e.g. eye drops) or MAO inhibitors should be kept under careful supervision. Inhalation anesthetics potentiate the cardiodepressive effect in patients who are being treated with β-receptor blockers. The dose of oral antidiabetic drugs may need to be adjusted for patients receiving β-blockers.