RANOLAZINE Drug Interactions: What You Need to Know

INTERACTIONS

• Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit Ranolazine Extended-Release Tablets to 500 mg twice daily. ( 7.1 )
• P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased.

Titrate Ranolazine

Extended-Release Tablets based on clinical response. ( 7.1 )

• CYP3A substrates: Limit simvastatin to 20 mg when used with Ranolazine Extended-Release Tablets. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with Ranolazine Extended-Release Tablets. ( 7.2 )
• OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with Ranolazine Extended-Release Tablets 1000 mg twice daily. Doses of other OCT2 substrates may require adjusted doses. ( 7.2 )
• Drugs transported by P-gp (e.g., digoxin), or drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses when used with Ranolazine Extended-Release Tablets. ( 7.2 )

See

17 for PATIENT COUNSELING INFORMATION and FDA-Approved Patient Labeling

7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use Ranolazine Extended-Release Tablets with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir <span class="opacity-50 text-xs">[see Contraindications (4) , Clinical Pharmacology (12.3) ]</span>. Moderate CYP3A Inhibitors Limit the dose of Ranolazine Extended-Release Tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ]</span>. P-gp Inhibitors Concomitant use of Ranolazine Extended-Release Tablets and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations.

Titrate Ranolazine

Extended-Release Tablets based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2) ]. CYP3A Inducers Do not use Ranolazine Extended-Release Tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort [see Contraindications (4) , Clinical Pharmacology (12.3) ].

7.2 Effects of Ranolazine on Other Drugs Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of Ranolazine Extended-Release Tablets to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as Ranolazine Extended-Release Tablets may increase plasma concentrations of these drugs <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

Drugs

Transported by P-gp Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see Clinical Pharmacology (12.3) ].

Drugs

Metabolized by CYP2D6 The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranolazine Extended-Release Tablets, and lower doses of these drugs may be required.

Drugs

Transported by OCT2 In subjects with type 2 diabetes mellitus, concomitant use of Ranolazine Extended-Release Tablets 1000 mg twice daily and metformin results in increased plasma levels of metformin.

When Ranolazine

Extended-Release Tablets 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with Ranolazine Extended-Release Tablets 500 mg twice daily [see Clinical Pharmacology (12.3) ].

7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use Ranolazine Extended-Release Tablets with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir <span class="opacity-50 text-xs">[see Contraindications (4) , Clinical Pharmacology (12.3) ]</span>. Moderate CYP3A Inhibitors Limit the dose of Ranolazine Extended-Release Tablets to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ]</span>. P-gp Inhibitors Concomitant use of Ranolazine Extended-Release Tablets and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations.

Titrate Ranolazine

Extended-Release Tablets based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2) ]. CYP3A Inducers Do not use Ranolazine Extended-Release Tablets with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort [see Contraindications (4) , Clinical Pharmacology (12.3) ].

7.2 Effects of Ranolazine on Other Drugs Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of Ranolazine Extended-Release Tablets to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as Ranolazine Extended-Release Tablets may increase plasma concentrations of these drugs <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>.

Drugs

Transported by P-gp Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see Clinical Pharmacology (12.3) ].

Drugs

Metabolized by CYP2D6 The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranolazine Extended-Release Tablets, and lower doses of these drugs may be required.

Drugs

Transported by OCT2 In subjects with type 2 diabetes mellitus, concomitant use of Ranolazine Extended-Release Tablets 1000 mg twice daily and metformin results in increased plasma levels of metformin.

When Ranolazine

Extended-Release Tablets 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with Ranolazine Extended-Release Tablets 500 mg twice daily [see Clinical Pharmacology (12.3) ].

Ranolazine extended-release tablets are contraindicated in patients: 1. Taking strong inhibitors of CYP3A [see Drug Interactions (7.1) ] 2. Taking inducers of CYP3A [see Drug Interactions (7.1) ] 3. With liver cirrhosis [see Use in Specific Populations (8.6) ] 4. Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) ( 4 , 7.1 ) 5. CYP3A inducers (e.g., rifampin, phenobarbital, St.John's wort) ( 4 , 7.1 ) 6. Liver cirrhosis ( 4 , 8.6 )

AND PRECAUTIONS

• QT interval prolongation: Can occur with ranolazine. Little data available on high doses, long exposure, use with QT interval-prolonging drugs, potassium channel variants causing prolonged QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. ( 5.1 )
• Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60mL/min). If acute renal failure develops, discontinue Ranolazine Extended-Release Tablets. ( 5.2 )

5.1 QT Interval Prolongation Ranolazine blocks I Kr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>. However, there is little experience with high doses (&gt;1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.

5.2 Renal Failure Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] &lt;30 mL/min) while taking Ranolazine Extended-Release Tablets. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue Ranolazine Extended-Release Tablets and treat appropriately <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) ]</span>. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL &lt;60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.

5.1 QT Interval Prolongation Ranolazine blocks I Kr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span>. However, there is little experience with high doses (&gt;1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.

5.2 Renal Failure Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] &lt;30 mL/min) while taking Ranolazine Extended-Release Tablets. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue Ranolazine Extended-Release Tablets and treat appropriately <span class="opacity-50 text-xs">[see Use in Specific Populations (8.7) ]</span>. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL &lt;60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.