General

Drug-drug:

• Concurrent use of Class Ia antiarrhythmics (including procainamide and quinidine) or Class III antiarrhythmics (including amiodarone, dofetilide, dronedarone, and sotalol) ↑ risk of cardiac arrhythmias; concurrent use contraindicated.
• Concurrent use of strong CYP3A inducers including carbamazepine, phenobarbital, phenytoin, and rifampin may ↓ levels and effectiveness; concurrent use not recommended.
• May ↑ levels and risk of toxicity with P-glycoprotein substrates including digoxin (↓ digoxin dose by 30% and monitor digoxin levels), colchicine, dabigatran, and phenytoin (monitor drug levels, consider dose reduction/titration).
• May ↑ levels and risk of toxicity with CYP2D6 substrates including metoprolol, tricyclic antidepressants , and phenothiazines; monitor drug levels, consider dose ↓/titration.

Drug-Natural Products:

• St. John's wort may ↓ levels and effectiveness; concurrent use not recommended.
• Grapefruit/grapefruit juice↑ risk of cardiac arrhythmias; concurrent ingestion contraindicated.

For extensive metabolizers (EMs)

Drug-drug:

• Concurrent use of strong or moderate CYP2D6 inhibitors and strong or moderate CYP3A inhibitors↑ risk of cardiac arrhythmias; concurrent use contraindicated.
• Concurrent use of strong CYP2D6 inhibitors including paroxetine↑ risk of potentially serious cardiac events; once daily dosing recommended.
• Concurrent use of moderate CYP2D6 inhibitors including terbinafine↑ risk of potentially serious cardiac events; once daily dose recommended.
• Concurrent use of strong CYP3A inhibitors including ketoconazole↑ risk of potentially serious cardiac events; once daily dose recommended.
• Concurrent use of moderate CYP3A inhibitors including fluconazole↑ risk of potentially serious cardiac events; once daily dose recommended.

For intermediate metabolizers (IMs)

Drug-drug:

• Concurrent use of strong or moderate CYP2D6 inhibitors and strong or moderate CYP3A inhibitors↑ risk of cardiac arrhythmias; concurrent use contraindicated.
• Concurrent use of strong CYP3A inhibitors, including ketoconazole, ↑ risk of cardiac arrhythmias; concurrent use contraindicated.
• Concurrent use of strong CYP2D6 inhibitors including paroxetine↑ risk of potentially serious cardiac events; once daily dose recommended.
• Concurrent use of moderate CYP2D6 inhibitors including terbinafine↑ risk of potentially serious cardiac events; once daily dose recommended.
• Concurrent use of moderate CYP3A inhibitors including fluconazole↑ risk of potentially serious cardiac events; concurrent use not recommended.

For poor metabolizers (PMs)

Drug-drug:

• Concurrent use of strong CYP3A inhibitors, including ketoconazole, ↑ risk of cardiac arrhythmias; concurrent use contraindicated.
• Concurrent use of moderate CYP3A inhibitors including fluconazole↑ risk of potentially serious cardiac events; concurrent use not recommended.
• Concurrent use of weak CYP3A inhibitors↑ risk of potentially serious cardiac events; concurrent use not recommended.