Ranexa Drug Interactions

Effects of other medicinal products on ranolazine: CYP3A4 or P-gp inhibitors: 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, posaconazole, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone) is contraindicated (see Contraindications). 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 Ranexa is recommended in patients treated with diltiazem and other moderately potent CYP3A4 inhibitors (e.g. erythromycin, fluconazole). Down-titration of Ranexa may be required (see Dosage & Administration and Precautions).
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 Ranexa is recommended in patients treated with P-gp inhibitors. Down-titration of Ranexa may be required (see Dosage & Administration and Precautions).
CYP3A4 inducers: Rifampicin (600 mg once daily) decreases ranolazine steady-state concentrations by approximately 95%. Initiation of treatment with Ranexa should be avoided during administration of inducers of CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St. John's Wort) (see Precautions).
CYP2D6 inhibitors: Ranolazine is partially metabolised 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 1000 mg 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%.
Effects of ranolazine on other medicinal products: 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 RANEXA may increase plasma concentrations of these drugs.
Available data suggest that ranolazine is a mild inhibitor of CYP2D6. Ranexa 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 Ranexa, 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: An increase in plasma digoxin concentrations by an average of 1.5-fold has been reported when Ranexa and digoxin are co-administered. Therefore, digoxin levels should be monitored following initiation and termination of Ranexa therapy.
Simvastatin: Simvastatin metabolism and clearance are highly dependent on CYP3A4. Ranexa 1000 mg twice daily increased plasma concentrations of simvastatin lactone, simvastatin acid by about 2 fold. Rhabdomyolysis has been associated with high doses of simvastatin and cases of rhabdomyolysis have been observed in patients receiving Ranexa and simvastatin, in postmarketing experience. Limit the dose of simvastatin to 20 mg once daily in patients taking any dose of Ranexa.
Atorvastatin: Ranexa 1000 mg 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 Ranexa. Dose limitation of other statins, metabolised by CYP3A4 (e.g. lovastatin), may be considered when taking Ranexa.
Tacrolimus, ciclosporin, sirolimus, everolimus: 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 Ranexa 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): Plasma exposure of metformin (1000 mg twice daily) increased 1.4- and 1.8-fold in subjects with type 2 diabetes mellitus when co-administered with RANEXA 500 mg and 1000 mg 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).