CV: QT interval prolongation, ARRHYTHMIA, heart block, palpitations.
Derm: rash.
EENT: oropharyngeal pain.
GI: diarrhea, flatulence, nausea, upper abdominal pain, constipation, gastroesophageal reflux.
MS: arthralgia, back pain, extremity pain.
Neuro: fatigue, headache, dizziness.
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.
Drug-Food:
- 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.
Therapeutic Classification:
Pharmacologic Classification: glucosylceramide synthase inhibitors
Absorption: EMs — 5% absorbed following oral administration (due to extensive first-pass metabolism).
Distribution: Distributes mainly into plasma.
Metabolism/Excretion: Extensively metabolized, primarily by the CYP2D6 isoenzyme, with some metabolism by the CYP3A4 isoenzyme; 41.8% excreted in urine and 51.4% in feces mostly as metabolites.
Half-life: EMs: 6.5 hr; PMs: 8.9 hr.