Razine Drug Interactions

Effects of Other Medicinal Products on Ranolazine: 500 mg tablet: Ranolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp).
CYP3A4 or P-gp inhibitors: 375 mg tablet: Ranolazine is a substrate of cytochrome CYP3A4. Inhibitors of CYP3A4 increase plasma concentrations of Ranolazine. The potential for dose-related adverse events (e.g. nausea, dizziness) may also increase with increased plasma concentrations. Concomitant treatment with ketoconazole 200 mg twice daily increased the AUC of Ranolazine by 3.0- to 3.9-fold during Ranolazine treatment. Combining Ranolazine with potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazole, parconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated. Grapefruit juice is also a potent CYP3A4 inhibitor. Diltiazem (180 to 360 mg once daily), a moderately potent CYP3A4 inhibitor, causes dose-dependent increases in average Ranolazine steady-state concentrations of 1.5- to 2.4-fold. Careful dose titration of Ranolazine is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranolazine may be required. Ranolazine is a substrate for P-gp. Inhibitors of P-gp (e.g. ciclosporin, verapamil) increase plasma levels of Ranolazine. Verapamil (120 mg three times daily) increases Ranolazine steady-state concentrations 2.2-fold. Careful dose titration of Ranolazine is recommended in patients treated with P-gp inhibitors. Down-titration of Ranolazine may be required.
CYP3A: 500 mg tablet: Do not use Ranolazine with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of Ranolazine 3.2-fold. Limit the dose of Ranolazine to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products. Diltiazem (180-360 mg daily) and verapamil (120 mg three times daily) increase Ranolazine steady-state plasma concentrations about 2-fold. Weak CYP3A inhibitors such as simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to Ranolazine in healthy volunteers.
P-gp inhibitors: 500 mg tablet: Down-titrate Ranolazine based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine.
CYP3A4 inducers: 375 mg tablet: Rifampicin (600 mg once daily) decreases Ranolazine steady-state concentrations by approximately 95%. Initiation of treatment with Ranolazine should be avoided during administration of inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort).
CYP3A and P-gp Inducers: 500 mg tablet: Avoid co-administration of Ranolazine and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John's wort. Rifampin (600 mg once daily) decreases the plasma concentration of Ranolazine (1 g twice daily) by approximately 95% by induction of CYP3A and, probably, P-gp.
CYP2D6 Inhibitors: 375 mg tablet: Ranolazine is partially metabolized by CYP2D6; therefore, inhibitors of this enzyme may increase plasma concentrations of Ranolazine. The potent CYP2D6 inhibitor paroxetine, at a dose of 20 mg once daily, increased steady-state plasma concentrations of Ranolazine 1 g twice daily by an average of 1.2-fold. No dose adjustment is required. At the dose level 500 mg twice daily, co-administration of a potent inhibitor of CYP2D6 could result in an increase in Ranolazine AUC of about 62%.
500 mg tablet: The potent CYP2D6 inhibitor, paroxetine (20 mg once daily), increases Ranolazine concentrations 1.2-fold. No dose adjustment of Ranolazine is required in patients treated with CYP2D6 inhibitors.
Effects of Ranolazine on other medicinal products: 375 mg tablet: Ranolazine is a moderate to potent inhibitor of P-gp and a mild inhibitor of CYP3A4, and may increase plasma concentrations of P-gp or CYP3A4 substrates. Tissue distribution of drugs which are transported by P-gp may be increased. Dose adjustment of sensitive CYP3A4 substrates (e.g., simvastatin, lovastatin) and CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, tacrolimus, sirolimus, everolimus) may be required as Ranolazine may increase plasma concentrations of these drugs. Available data suggest that Ranolazine is a mild inhibitor of CYP2D6. Ranolazine 750 mg twice daily increased plasma concentrations of metoprolol by 1.8-fold. Therefore, the exposure to metoprolol or other CYP2D6 substrates (e.g. propafenone and flecainide or, to a lesser extent, tricyclic antidepressants and antipsychotics) may be increased during co-administration with Ranolazine, and lower doses of these medicinal products may be required. The potential for inhibition of CYP2B6 has not been evaluated. Caution is advised during co-administration with CYP2B6 substrates (e.g. bupropion, efavirenz, cyclophosphamide).
Digoxin: 375 mg tablet: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported when Ranolazine and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of Ranolazine therapy.
500 mg tablet: Digoxin (0.125 mg) does not significantly alter Ranolazine levels.
Simvastatin: 375 mg tablet: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranolazine 1 g twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid by about 2 folds. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranolazine and simvastatin, in post-marketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranolazine.
Atorvastatin: 375 mg tablet: Ranolazine 1 g twice daily increased Cmax and AUC of atorvastatin 80 mg once daily by 1.4- and 1.3-fold, respectively and changed the Cmax and AUC of atorvastatin metabolites less than 35%. Dose limitation of atorvastatin and appropriate clinical monitoring may be considered when taking Ranolazine. Dose limitation of other statins, metabolized by CYP3A4 (e.g. lovastatin), may be considered when taking Ranolazine.
Tacrolimus, ciclosporin, sirolimus, everolimus: 375 mg tablet: Increased plasma concentrations of tacrolimus, a CYP3A4 substrate, have been observed in patients after Ranolazine administration. It is recommended that tacrolimus blood levels are monitored when co-administering Ranolazine and tacrolimus and that tacrolimus dosage is adjusted accordingly. This is also recommended for other CYP3A4 substrates with a narrow therapeutic range (e.g., ciclosporin, sirolimus, everolimus).
Drugs transported by the Organic Cation Transporter-2 (OCT2): 375 mg tablet: Plasma exposure of metformin (1 g twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when co-administered with Ranolazine 500 mg and 1 g twice daily, respectively. The exposure of other OCT2 substrates, including but not limited to pindolol and varenicline, may be affected to a similar degree. There is a theoretical risk that concomitant treatment of Ranolazine with other drugs known to prolong the QTc interval may give rise to a pharmacodynamic interaction and increase the possible risk of ventricular arrhythmias. Examples of such drugs include certain antihistamines (e.g. terfenadine, astemizole, mizolastine), certain antiarrhythmics (e.g. quinidine, disopyramide, procainamide), erythromycin, and tricyclic antidepressants (e.g. imipramine, doxepin, amitriptyline).
Effects of Ranolazine on Other Drugs: 500 mg tablet: In vitro studies indicate that Ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors. Ranolazine and its most abundant metabolites are not known to inhibit the metabolism of substrates for CYP 1A2, 2C8, 2C9, 2C19, or 2E1 in human liver microsomes, suggesting that Ranolazine is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.
Drugs Metabolized by CYP3A: 500 mg tablet: The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each increased about 2-fold in healthy subjects receiving simvastatin (80 mg once daily) and Ranolazine (1 g twice daily). Dose adjustments of simvastatin are not required when Ranolazine is co-administered with simvastatin. The pharmacokinetics of diltiazem is not affected by Ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and Ranolazine 1 g twice daily.
Drugs Transported by P-gp: 500 mg tablet: Ranolazine (1 g twice daily) causes a 1.5-fold elevation of digoxin plasma concentrations. The dose of digoxin may have to be adjusted.
Drugs Metabolized by CYP2D6: 500 mg tablet: Ranolazine or its metabolites partially inhibit CYP2D6. There are no studies of concomitant use of Ranolazine with other drugs metabolized by CYP2D6, such as tricyclic antidepressants and antipsychotics, but lower doses of CYP2D6 substrates may be required.