Ranexa, 500 mg, extended-release film-coated tablets, 60 pcs.
Concomitant use is contraindicated
Potent CYP3A4 inhibitors
Ranolazine is a substrate of cytochrome CYP3A4. Concomitant use with inhibitors of CYP3A4 isoenzyme activity increases the concentration of ranolazine in the blood plasma. Potential dose-dependent side effects (eg, nausea, dizziness) may also increase with increasing plasma concentrations of the drug. Simultaneous treatment with ketoconazole 200 mg 2 times a day increases the AUC of ranolazine by 3-3.9 times.
The simultaneous use of ranolazine and potent inhibitors of the CYP3A4 isoenzyme (for example, itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated.
Grapefruit juice is also a potent inhibitor of the CYP3A4 isoenzyme.
Concomitant use with caution
Medium strength inhibitors of the CYP3A4 isoenzyme
Diltiazem (180-360 mg 1 time / day), an inhibitor of the CYP3A4 isoenzyme of moderate strength, causes, depending on the dose, an increase in the average Css value of ranolazine in blood plasma by 1.5-2.4 times. For patients receiving diltiazem and other moderately potent CYP3A4 inhibitors (e.g., erythromycin, fluconazole), dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary.
Inducers of CYP3A4 isoenzyme activity
Concomitant use of ranolazine with inducers of CYP3A4 isoenzyme activity (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort (Hypericum perforatum)) may lead to a decrease in the effectiveness of the drug. For example, rifampicin (600 mg 1 time / day) reduces the Css of ranolazine in blood plasma by approximately 95%. Therefore, the use of ranolazine should not be started in patients receiving treatment with inducers of the CYP3A4 isoenzyme.
P-glycoprotein inhibitors
Ranolazine is a P-glycoprotein (P-gp) substrate. P-gp inhibitors (eg, cyclosporine, verapamil) increase ranolazine plasma concentrations. Verapamil (120 mg 3 times/day) increases the Css of ranolazine by 2.2 times. For patients receiving treatment with P-gp inhibitors, dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary. On the other hand, ranolazine is a moderate P-gp inhibitor and a weak CYP3A4 inhibitor and may increase plasma concentrations of P-gp or CYP3A4 substrates. The tissue distribution of drugs that are transported by P-gp may be increased.
Substrates of the CYP2D6 isoenzyme
There is evidence that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. Taking ranolazine 750 mg 2 times a day increases the concentration of metoprolol in the blood plasma by 1.8 times. Therefore, when used simultaneously with ranolazine, the effect of metoprolol or other substrates of the CYP2D6 isoenzyme (for example, propafenone and flecainide, to a lesser extent, tricyclic antidepressants and antipsychotics) may be enhanced; therefore, a dose reduction of these drugs may be required.
Substrates of the CYP2B6 isoenzyme
The potential to inhibit the CYP2B6 isoenzyme has not been established. Caution is recommended when administered together with substrates of the CYP2B6 isoenzyme (for example, bupropion, efavirenz, cyclophosphamide).
Digoxin
There is evidence of an increase in the concentration of digoxin in the blood plasma by an average of 1.5 times with the simultaneous use of digoxin and ranolazine. Therefore, it is necessary to monitor digoxin levels at the beginning and after the end of ranolazine therapy.
Substars of the CYP3A4 isoenzyme
Ranolazine is a weak CYP3A4 inhibitor, which may result in increased plasma concentrations of CYP3A4 substrates and may require dose adjustment for sensitive CYP3A4 substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic index (e.g., cyclosporine, tacrolimus, sirolimus , everolimus).
Simvastatin
The metabolism and clearance of simvastatin is highly dependent on the CYP3A4 isoenzyme. Taking ranolazine 1000 mg 2 times a day increases the concentration of simvastatin lactone, simvastatin acid, which increases the inhibition of HMG-CoA reductase by 1.4-1.6 times. Taking simvastatin in high doses is associated with the development of rhabdomyolysis, and cases of rhabdomyolysis have also been described with the simultaneous use of ranolazine and simvastatin. The maximum dose of simvastatin for patients concomitantly taking ranolazine should not exceed 20 mg/day. For other statins metabolized by the CYP3A4 isoenzyme (lovastatin), dose limitation is possible.
Tacrolimus, cyclosporine, sirolimus, everolimus
An increase in plasma concentrations of tacrolimus, a substrate of the CYP3A4 isoenzyme, was observed in patients receiving ranolazine. When tacrolimus and ranolazine are used concomitantly, it is recommended to monitor the concentration of tacrolimus in the blood plasma and, if necessary, adjust the dose. This approach is also recommended for other CYP3A4 substrates with a narrow therapeutic index (for example, cyclosporine, sirolimus, everolimus).
Drugs that prolong the QT interval
There is a theoretical possibility that with simultaneous use of ranolazine and other drugs that prolong the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. These drugs include certain antihistamines (eg, terfenadine, astemizole, mizolastine), certain antiarrhythmics (eg, quinidine, disopyramide, procainamide), and erythromycin and tricyclic antidepressants (eg, imipramine, doxepin, amitriptyline).
Ranolazine*
Amitriptyline.
There is a theoretical possibility that when ranolazine is used concomitantly with amitriptyline, a tricyclic antidepressant that prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of ventricular arrhythmias may increase. Caution must be exercised when treating patients receiving amitriptyline.
Astemizole.
There is a theoretical possibility that with the simultaneous use of ranolazine and astemizole, an antihistamine that prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Caution must be exercised when treating patients receiving astemizole.
Bupropion.
The potential to inhibit the CYP2B6 isoenzyme has not been established. Caution is recommended when prescribing ranolazine together with the CYP2B6 isoenzyme substrate bupropion.
Verapamil.
Ranolazine is a P-glycoprotein substrate. P-glycoprotein inhibitors increase the concentration of ranolazine in the blood plasma. Verapamil (120 mg three times daily) increases the Css of ranolazine by 2.2 times. Caution should be exercised when administering ranolazine concomitantly with the P-gp inhibitor verapamil. For patients receiving treatment with verapamil, a P-gp inhibitor, dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary.
Voriconazole.
Ranolazine is a substrate of cytochrome CYP3A4. Concomitant use with inhibitors of CYP3A4 isoenzyme activity increases the concentration of ranolazine in the blood plasma. Potential dose-related side effects (eg, nausea, dizziness) may also increase as ranolazine plasma concentrations increase. The simultaneous use of ranolazine and the strong CYP3A4 isoenzyme inhibitor voriconazole is contraindicated.
Digoxin.
There is evidence of an increase in the concentration of digoxin in the blood plasma by an average of 1.5 times with the simultaneous use of digoxin and ranolazine. Therefore, it is necessary to monitor digoxin levels at the beginning and after the end of therapy using ranolazine.
Disopyramide.
There is a theoretical possibility that with the simultaneous use of ranolazine and the antiarrhythmic drug disopyramide, which prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Caution must be exercised when treating patients receiving disopyramide.
Diltiazem
(180-360 mg once a day) is an inhibitor of the CYP3A4 isoenzyme of moderate strength, causing, depending on the dose, an increase in the average Css of ranolazine by 1.5-2.4 times. Caution should be exercised when ranolazine is used concomitantly with diltiazem. Dosage titration of ranolazine is recommended for patients treated with diltiazem. A dose reduction of ranolazine may be necessary.
Doxepin.
There is a theoretical possibility that with simultaneous use of ranolazine and the tricyclic antidepressant doxepin, which prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Caution should be exercised when treating patients receiving doxepin.
Imipramine.
There is a theoretical possibility that with simultaneous use of ranolazine and imipramine, a tricyclic antidepressant that prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Caution must be exercised when treating patients receiving imipramine.
Itraconazole
Ranolazine is a substrate of cytochrome CYP3A4. Concomitant use with inhibitors of CYP3A4 isoenzyme activity increases the concentration of ranolazine in the blood plasma. Potential dose-related side effects (eg, nausea, dizziness) may also increase as ranolazine plasma concentrations increase. The simultaneous use of ranolazine and itraconazole, a strong inhibitor of the CYP3A4 isoenzyme, is contraindicated.
Carbamazepine.
The simultaneous use of ranolazine with carbamazepine, an inducer of the activity of the CYP3A4 isoenzyme, may lead to a decrease in its effectiveness. Therefore, ranolazine should not be started in patients receiving carbamazepine. Caution should be exercised when using ranolazine concomitantly with carbamazepine.
Ketoconazole
. Ranolazine is a substrate of cytochrome CYP3A4. Concomitant use with inhibitors of CYP3A4 isoenzyme activity increases the concentration of ranolazine in the blood plasma. Potential dose-related side effects (eg, nausea, dizziness) may also increase as ranolazine plasma concentrations increase. Simultaneous treatment with ketoconazole 200 mg 2 times a day increases the AUC of ranolazine by 3-3.9 times. The simultaneous use of ranolazine and ketoconazole, a strong inhibitor of the CYP3A4 isoenzyme, is contraindicated.
Clarithromycin.
Potential dose-related side effects (eg, nausea, dizziness) may also increase as ranolazine plasma concentrations increase. The simultaneous use of ranolazine and clarithromycin, a strong inhibitor of the CYP3A4 isoenzyme, is contraindicated.
Lovastatin.
Ranolazine is a weak inhibitor of the CYP3A4 isoenzyme, which may lead to an increase in the concentration of lovastatin, a sensitive substrate of the CYP3A4 isoenzyme, in the blood plasma and require dose adjustment.
Metoprolol.
There is evidence that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. The use of ranolazine 750 mg 2 times a day increases the concentration of metoprolol in the blood plasma by 1.8 times. Therefore, when used simultaneously with ranolazine, the effect of metoprolol, a substrate of the CYP2D6 isoenzyme, may be enhanced, which may require a reduction in the dose of this drug.
Posaconazole
. Ranolazine is a substrate of cytochrome CYP3A4. Concomitant use with inhibitors of CYP3A4 isoenzyme activity increases the concentration of ranolazine in the blood plasma. Potential dose-related side effects (eg, nausea, dizziness) may also increase as ranolazine plasma concentrations increase. Concomitant use of ranolazine and the strong CYP3A4 inhibitor posaconazole is contraindicated.
Procainamide.
There is a theoretical possibility that with the simultaneous use of ranolazine and procainamide, an antiarrhythmic drug that prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Caution must be exercised when treating patients receiving procainamide treatment.
Propaphenone.
There is evidence that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. When used simultaneously with ranolazine, the effect of propafenone, a substrate of the CYP2D6 isoenzyme, may be enhanced, which may require a reduction in the dose of this drug.
Rifampicin.
The simultaneous use of ranolazine with rifampicin, an inducer of the activity of the CYP3A4 isoenzyme, may lead to a decrease in its effectiveness. For example, rifampicin (600 mg once daily) reduces the steady-state plasma concentration of ranolazine by approximately 95%. Therefore, ranolazine should not be started in patients receiving rifampicin. Caution should be exercised when administering ranolazine concomitantly with rifampicin.
Simvastatin.
Ranolazine is a weak inhibitor of the CYP3A4 isoenzyme, which may lead to increased plasma concentrations of simvastatin, a sensitive substrate of the CYP3A4 isoenzyme, and require dose adjustment. The metabolism and clearance of simvastatin is highly dependent on the CYP3A4 isoenzyme. The use of ranolazine 1000 mg 2 times a day increases the concentration of lactone, simvastatin, simvastatin acid, which increases the inhibition of HMG-CoA reductase by 1.4-1.6 times. The use of simvastatin in high doses is associated with the development of rhabdomyolysis, and cases of rhabdomyolysis have also been described with the simultaneous use of ranolazine and simvastatin. The maximum dose of simvastatin for patients concomitantly taking ranolazine should not exceed 20 mg/day.
Sirolimus.
When sirolimus and ranolazine are used concomitantly, it is recommended to monitor the plasma concentrations of sirolimus and adjust the dose if necessary.
Sotalol.
Concomitant use of ranolazine with sotalol is contraindicated.
Tacrolimus.
Ranolazine is a weak inhibitor of the CYP3A4 isoenzyme, which may lead to increased plasma concentrations of tacrolimus, a CYP3A4 substrate with a narrow therapeutic range, and require dose adjustment. When using tacrolimus and ranolazine concomitantly, it is recommended to monitor the concentration of tacrolimus in the blood plasma and, if necessary, adjust the dose.
Terfenadine.
There is a theoretical possibility that with the simultaneous use of ranolazine and terfenadine, an antihistamine that prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. Caution must be exercised when treating patients receiving terfenadine.
Phenytoin, phenobarbital.
The simultaneous use of ranolazine with phenobarbital or phenytoin, an inducer of the activity of the CYP3A4 isoenzyme, may lead to a decrease in its effectiveness. Therefore, ranolazine should not be started in patients receiving these drugs. Caution must be exercised during simultaneous use.
Fluconazole.
For patients receiving fluconazole, a moderate-potency inhibitor of the CYP3A4 isoenzyme, dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary. Caution should be exercised when using ranolazine concomitantly with fluconazole.
Quinidine.
There is a theoretical possibility that with the simultaneous use of ranolazine and quinidine, an antiarrhythmic drug that prolongs the QT interval, a pharmacodynamic interaction may occur and the risk of developing ventricular arrhythmias may increase. The simultaneous use of ranolazine with quinidine, a class IA antiarrhythmic drug, is contraindicated.
Cyclosporine.
Ranolazine is a weak inhibitor of the CYP3A4 isoenzyme, which may lead to increased plasma concentrations of cyclosporine, a substrate of the CYP3A4 isoenzyme with a narrow therapeutic range, and require dose adjustment.
Cyclophosphamide.
The potential to inhibit the CYP2B6 isoenzyme has not been established. When prescribing ranolazine together with cyclophosphamide, a substrate of the CYP2B6 isoenzyme, caution is recommended.
Everolimus.
When administering everolimus and ranolazine concomitantly, it is recommended to monitor the plasma concentrations of everolimus and adjust the dose if necessary.
Erythromycin.
For patients receiving erythromycin, a moderate-potency inhibitor of the CYP3A4 isoenzyme, dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary. Caution should be exercised when using ranolazine concomitantly with erythromycin.
Efavirenz. The potential to inhibit the CYP2B6 isoenzyme has not been established. When prescribing ranolazine together with efavirenz, a substrate of the CYP2B6 isoenzyme, caution is recommended.
