3. Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for ivacaftor are summarized in Table 19. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
|---|---|---|---|---|
| ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | strong CYP3A inhibitors (e.g., ketoconazole, voriconazole, posaconazole, telithromycin, clarithromycin) | concurrent use significantly increased ivacaftor exposure (8.5-fold ↑ in AUC with ketoconazole); adjunctive administration may significantly increase elexacaftor, tezacaftor and ivacaftor concentrations and ↑ potential for enhanced pharmacologic/adverse effects | reduce elexacaftor, ivacaftor, tezacaftor dosages and monitor for efficacy and adverse events | 2-major (CP) major (DrugReax) |
| ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | moderate CYP3A inhibitors (e.g., fluconazole) | concurrent use increased ivacaftor exposure (3-fold ↑ AUC with fluconazole); adjunctive administration may significantly increase tezacaftor and ivacaftor concentrations and ↑ potential for enhanced pharmacologic/adverse effects | reduce elexacaftor, ivacaftor, tezacaftor dosages and monitor for efficacy and adverse events | 2-major (CP) moderate (DrugReax) |
| ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | strong CYP3A inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin, St. John’s wort) | concurrent use decreased ivacaftor exposure [9-fold ↓ AUC with rifampin (57% ↓)]; adjunctive administration may significantly reduce elexacaftor, tezacaftor and ivacaftor concentrations (CYP3A substrates) and ↓ efficacy | strong CYP3A inducers should be avoided while taking ivacaftor, lumacaftor/ ivacaftor, tezacaftor/ ivacaftor, and elexacaftor/ tezacaftor/ ivacaftor | 2-major (CP) major (DrugReax) |
| ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | CYP3A and/or P-glycoprotein (P-gp) substrates (e.g., midazolam, alprazolam, cyclosporine, tacrolimus) | ivacaftor may be a weak CYP3A and P-gp transport inhibitor; concurrent use with midazolam ↑ midazolam AUC 1.5-fold and ↑ digoxin AUC 1.3-fold |
use with caution and monitor drug- related side effects and/or monitor therapeutic levels | tacrolimus: 2-major; others - 3-moderate (CP) moderate (DrugReax) |
| lumacaftor/ivacaftor | CYP3A substrates (e.g., antibiotics, antifungals, antivirals) | lumacaftor is strong CYP3A inducer; concurrent use may result in reduced efficacy of CYP3A substrates | consider alternative antibiotics such as azithromycin, ciprofloxacin, or levofloxacin whenever possible; if an antifungal is required, monitor for breakthrough fungal infection; consider alternative treatment with fluconazole whenever possible; may also adjust lumacaftor/ivacaftor dosages or avoid combination, if possible | major (DrugReax) 2-major (CP) |
| lumacaftor/ivacaftor | hormonal contraceptives | concurrent administration may reduce hormonal contraceptive exposure and efficacy and may increase menstruation-associated adverse events (e.g., menorrhagia) | avoid concurrent use; use alternate methods of birth control | major (DrugReax) 2-major (CP) |
| ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, elexacaftor/tezacaftor/ivacaftor | warfarin | warfarin exposure may be modified with adjunctive lumacaftor/ ivacaftor administration, as lumacaftor/ ivacaftor is a CYP3A4 inducer, the enzyme that metabolizes R-warfarin, and ivacaftor may be a weak CYP2C9 inhibitor, the primary enzyme that metabolizes S-warfarin | monitor international normalized ratio and adjust warfarin dosages as needed | moderate (DrugReax) 3-moderate (C |
Legend:
- *CP = Clinical Pharmacology
- AUC = area under the curve