Description of the drug RANEXA® (RANEXA)
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 (including itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated.
Grapefruit juice is also a potent inhibitor of the CYP3A4 isoenzyme.
Diltiazem (180-360 mg 1 time / day), an inhibitor of the CYP3A4 isoenzyme of moderate potency, 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.
The simultaneous use of ranolazine with inducers of the activity of the CYP3A4 isoenzyme (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort) may lead to a decrease in the effectiveness of ranolazine. 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.
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.
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.
The potential to inhibit the CYP2B6 isoenzyme has not been established. Caution is recommended during administration with CYP2B6 substrates (eg, bupropion, efavirenz, cyclophosphamide).
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.
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).
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).
Ranexa
Ranolazine is a substrate of cytochrome CYP3A4. The simultaneous use of ranolazine with inhibitors of the CYP3A4 isoenzyme increases the concentration of ranolazine in the blood plasma. The likelihood of developing dose-related side effects (eg, nausea, dizziness) may also increase with increasing ranolazine plasma concentrations.
Simultaneous use is contraindicated:
Strong CYP3A4 inhibitors
The simultaneous use of ranolazine and strong inhibitors of the CYP3A4 isoenzyme (for example, itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated. Grapefruit juice is also a strong CYP3A4 inhibitor.
Concomitant use with caution:
Moderate CYP3A4 inhibitors
Diltiazem (180-360 mg once daily), a moderate inhibitor of the CYP3A4 isoenzyme, causes a dose-dependent increase in mean steady-state concentrations of ranolazine by 1.5-2.4 times.
For patients receiving treatment with diltiazem and other moderate inhibitors of the CYP3A4 isoenzyme (for example, erythromycin, fluconazole), dose titration of ranolazine is recommended. A dose reduction of ranolazine may be necessary.
Inducers of the CYP3A4 isoenzyme
Patients receiving treatment with inducers of the CYP3A4 isoenzyme (rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort (Hypericum perforatum)) should not start taking ranolazine.
CYP2D6 isoenzyme inhibitors
Ranolazine is partially metabolized by the CYP2D6 isoenzyme. The simultaneous use of ranolazine with inhibitors of the CYP2D6 isoenzyme may lead to increased concentrations of ranolazine in the blood plasma. The simultaneous use of ranolazine 1000 mg 2 times a day with a strong inhibitor of the CYP2D6 isoenzyme paroxetine 20 mg 1 time a day increases the average concentration of ranolazine in blood plasma at steady state by approximately 1.2 times. No dose adjustment is required. Concomitant use of ranolazine 500 mg twice daily and a strong CYP2D6 inhibitor may result in an increase in the AUC of ranolazine by approximately 62%.
P-gp inhibitors/substrates (P-glycoprotein)
Ranolazine is a P-gp substrate. P-gp inhibitors (eg, cyclosporine, verapamil) increase ranolazine plasma concentrations. Verapamil (120 mg three times daily) increases the steady-state concentration 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 may increase plasma concentrations of P-gp 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. When used concomitantly 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, which may require a reduction in the dose of these drugs.
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 concentrations at the beginning and after the end of therapy with ranolazine.
CYP3A4 isoenzyme substrates
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 and simvastatin acid in the blood plasma by approximately 2 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.
Atorvastatin
When ranolazine and atorvastatin are used concomitantly, a dose reduction of atorvastatin and appropriate clinical monitoring may be required.
Other statins metabolized by CYP3A4 (lovastatin) may require dose adjustment.
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 tacrolimus plasma concentrations 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).
Organic cation transporter 2 (OCT2) substrates
With the simultaneous use of ranolazine 500 mg and 1000 mg 2 times a day and metformin 1000 mg 2 times a day, the concentration of metformin in the blood plasma in patients with type 2 diabetes mellitus increases by 1.4 and 1.8 times, respectively. Plasma concentrations of other OCT2 substrates, including pindolol and varenicline, may increase when administered concomitantly with ranolazine.
Drugs that prolong the QTc interval
There is a theoretical possibility that with simultaneous use of ranolazine and other drugs that prolong the QTc 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).
Instructions for use RANOLAZINE-NAN
Effect of other drugs on ranolazine
CYP3A4 or P-gp inhibitors.
Ranolazine is a substrate of cytochrome CYP3A4. CYP3A4 inhibitors increase ranolazine plasma concentrations. Potential dose-dependent side effects (eg, nausea, dizziness) may also increase with increasing plasma concentrations of the drug. Concomitant treatment with ketoconazole at a dose of 200 mg 2 times a day increases the AUC of ranolazine by 3–3.9 times during treatment with ranolazine. Concomitant use of ranolazine and strong CYP3A4 inhibitors (eg, itraconazole, ketoconazole, voriconazole, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated. Grapefruit juice is also a potent inhibitor of CYP3A4.
Diltiazem (at a dose of 180-360 mg 1 time / day), an inhibitor of CYP3A4 of moderate potency, causes a dose-dependent increase in the mean Css of ranolazine by 1.5-2.4 times. For patients receiving treatment with diltiazem and other moderately potent CYP3A4 inhibitors (eg, erythromycin, fluconazole), careful dose titration of ranolazine is recommended. The dose of ranolazine may need to be reduced.
Ranolazine is a P-gp substrate. P-gp inhibitors (eg, cyclosporine, verapamil) increase ranolazine plasma concentrations. Verapamil (at a dose of 120 mg 3 times a day) increases the Css of ranolazine by 2.2 times. For patients receiving treatment with P-gp inhibitors, careful dose titration of ranolazine is recommended. The dose of ranolazine may need to be reduced.
CYP3A4 inducers.
Rifampin (at a dose of 600 mg 1 time / day) reduces the Css of ranolazine by approximately 95%. Treatment with ranolazine should not be initiated while taking CYP3A4 inducers (eg, rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's wort).
CYP2D6 inhibitors.
Ranolazine is partially metabolized by the CYP2D6 isoenzyme; therefore, inhibitors of this isoenzyme may increase ranolazine plasma concentrations. A strong CYP2D6 inhibitor, paroxetine, at a dose of 20 mg 1 time / day, increases the average concentration of ranolazine in the blood plasma at steady state by approximately 1.2 times (when taking ranolazine 1000 mg 2 times / day). No dose adjustment is required. At the dose level of 500 mg twice daily, coadministration of a strong CYP2D6 inhibitor may result in an increase in ranolazine AUC of approximately 62%.
Effect of ranolazine on other drugs
Ranolazine is a moderate to strong P-gp inhibitor and a weak CYP3A4 inhibitor, and may increase plasma concentrations of P-gp or CYP3A4 substrates. The tissue distribution of drugs transported by P-gp may be increased.
Dosage adjustments may be required for CYP3A4 substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus, everolimus) because ranolazine may increase plasma concentrations of these drugs.
Available data indicate that ranolazine is a weak inhibitor of the CYP2D6 isoenzyme. Taking ranolazine 750 mg 2 times a day increases the plasma concentration of metoprolol by 1.8 times. Therefore, when administered concomitantly with ranolazine, exposure to metoprolol or other CYP2D6 substrates (e.g., propafenone and flecainide or, to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased, which may require a dose reduction of these medications.
The potential to inhibit the CYP2B6 isoenzyme has not been established. Caution is recommended when coadministered with CYP2B6 substrates (eg, 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 concentrations at the beginning and at the end of ranolazine therapy.
Simvastatin.
The metabolism and clearance of simvastatin is highly dependent on the CYP3A4 isoenzyme. Taking ranolazine at a dose of 1000 mg 2 times a day increases the concentration of simvastatin lactone and simvastatin acid in plasma by 2 times. Taking simvastatin in high doses is associated with the development of rhabdomyolysis; cases of rhabdomyolysis have also been described with the simultaneous use of ranolazine and simvastatin. The maximum dose of simvastatin for patients taking ranolazine should not exceed 20 mg 1 time / day.
Atorvastatin.
Taking ranolazine at a dose of 1000 mg 2 times a day increases the Cmax and AUC of atorvastatin taken at a dose of 80 mg 1 time a day by 1.4 and 1.3 times, respectively. In this case, the Cmax and AUC of atorvastatin metabolites changes by less than 35%. Appropriate clinical monitoring and dose limitation of atorvastatin may be required when taking Ranolazine-NAN.
For other statins metabolized by the CYP3A4 isoenzyme (lovastatin), dose limitation may be required when taking ranolazine.
Tacrolimus, cyclosporine, sirolimus, everolimus.
During the use of ranolazine, patients experienced an increase in plasma concentrations of tacrolimus, a substrate of the CYP3A4 isoenzyme. When tacrolimus and ranolazine are used concomitantly, it is recommended to monitor the concentration of tacrolimus in the blood plasma and, if necessary, adjust its dose. This approach is also recommended for other CYP3A4 substrates with a narrow therapeutic index (for example, cyclosporine, sirolimus, everolimus).
Drugs transported by organic cation transporter-2 (OCT2).
Plasma exposure to metformin (at a dose of 1000 mg 2 times / day) increased by 1.4 and 1.8 times in patients with diabetes mellitus while taking ranolazine at doses of 500 mg and 1000 mg 2 times / day, respectively. Ranolazine may interfere with exposure to other OCT2 substrates, including pindolol and varenicline.
There is a theoretical risk that concomitant treatment with ranolazine and other drugs that prolong the QTc interval may result in a pharmacodynamic interaction and increase the risk of ventricular arrhythmias. These drugs include certain antihistamines (eg, terfenadine, astemizole, mizolastine), certain antiarrhythmics (eg, quinidine, disopyramide, procainamide), erythromycin, and tricyclic antidepressants (eg, imipramine, doxepin, amitriptyline).
